bims-flamet 2023-04-30 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2023–04–30
forty-five papers selected by
Peio Azcoaga, Biodonostia HRI

Modulation of T-cell function by myeloid-derived suppressor cells in hematological malignancies.
Novel Therapeutic Targets for Tumor Microenvironment in Cancer.
TU-100 Antagonizes the M2 Polarization Phenotype of Macrophages in the Tumor Microenvironment by Suppressing the TLR4/NF-B/STAT3 Axis.
Advances in research on immune escape mechanism of glioma.
Tumor-derived Small Extracellular Vesicles Inhibit the Efficacy of CAR T Cells against Solid Tumors.
Strategies to overcome myeloid cell induced immune suppression in the tumor microenvironment.
Insights into the potential of Sanguinarine as a promising therapeutic option for breast cancer.
Ruth Scherz-Shouval: Together we can ask big questions.
Tumor-associated macrophages: Prognostic and therapeutic targets for cancer in humans and dogs.
Transforming Growth Factor-β1 in Cancer Immunology: Opportunities for Immunotherapy.
Dual antitumor immunomodulatory effects of PARP inhibitor on the tumor microenvironment: A counterbalance between anti-tumor and pro-tumor.
Tumor-Associated Macrophage Subsets: Shaping Polarization and Targeting.
Cancer Resistance to Immunotherapy: Comprehensive Insights with Future Perspectives.
Editorial: The interconnection between epigenetic modifications and the tumor microenvironment.
Engineered anti-prostate cancer CAR-neutrophils from human pluripotent stem cells.
Therapeutic Potential of Tumor Metabolic Reprogramming in Triple-Negative Breast Cancer.
Harnessing novel strategies and cell types to overcome immune tolerance during adoptive cell therapy in cancer.
Tumor-host colluding through erythroid progenitor cells: Mechanisms and opportunities.
The tumor microenvironment in the postsurgical liver: Mechanisms and potential targets of postoperative recurrence in human hepatocellular carcinoma.
Carcinoma-associated fibroblast-like tumor cells remodel the Ewing sarcoma tumor microenvironment.
[Research Progress on the Role of Tumor-Associated Macrophages in Multiple Myeloma --Review].
The critical immune basis for differential responses to immunotherapy in primary versus metastatic pancreatic cancer.
COPS6 promotes tumor progression and reduces CD8+ T cell infiltration by repressing IL-6 production to facilitate tumor immune evasion in breast cancer.
TIGIT in Lung Cancer: Potential Theranostic Implications.
Infiltration by Intratumor and Stromal CD8 and CD68 in Cervical Cancer.
Correction: Programmed death ligand 1-positive immune cells in primary tumor or metastatic axillary lymph nodes can predict prognosis of triple-negative breast cancer even when present at < 1% in the tumor region.
Immune mechanisms of toxicity from checkpoint inhibitors.
Key aspects for conception and construction of co-culture models of tumor-stroma interactions.
Targeting fibrinogen-like protein 1 enhances immunotherapy in hepatocellular carcinoma.
IL-1β Is an Androgen-Responsive Target in Macrophages for Immunotherapy of Prostate Cancer.
The "Self-eating" of cancer-associated fibroblast: A potential target for cancer.
Programmed cell death-1 receptor-mediated regulation of Tbet+NK1.1- innate lymphoid cells within the tumor microenvironment.
TNF-Alpha Promotes an Inflammatory Mammary Microenvironment That Favors Macrophage and Epithelial Migration in a CCL2- and Mitochondrial-ROS-Dependent Manner.
The Diet as a Modulator of Tumor Microenvironment in Colorectal Cancer Patients.
Advances in Stem Cell Immunotherapy.
Recruiting T Cells towards Brain for Enhanced Glioblastoma Immunotherapeutic Efficacy by Co-delivery of Cytokines and Immune Checkpoint Antibodies with Macrophage Membrane-Camouflaged Nano Vesicles.
The characterization of the sensitive ovarian cancer cell lines A2780 and W1 in response to ovarian CAFs.
Overcoming resistance to immunotherapy by targeting GPR84 in myeloid-derived suppressor cells.
Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses.
The "Great Debate" at Immunotherapy Bridge 2022, Naples, November 30th-December 1st, 2022.
Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF-nuclear IL-33-GATA3 pathway.
Regulation of cGAS-STING signalling in cancer: Approach for combination therapy.
A metabolic clue for STING suppression.
Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer.
Anti-tumor Efficacy of CD19 CAR-T in a Raji B Cell Xenografted Mouse Model.

Front Cell Dev Biol. 2023 ;11 1129343

Modulation of T-cell function by myeloid-derived suppressor cells in hematological malignancies.

Vaishali Bhardwaj, Stephen M Ansell.

  Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes that negatively regulate the immune response to cancer and chronic infections. Abnormal myelopoiesis and pathological activation of myeloid cells generate this heterogeneous population of myeloid-derived suppressor cells. They are characterized by their distinct transcription, phenotypic, biochemical, and functional features. In the tumor microenvironment (TME), myeloid-derived suppressor cells represent an important class of immunosuppressive cells that correlate with tumor burden, stage, and a poor prognosis. Myeloid-derived suppressor cells exert a strong immunosuppressive effect on T-cells (and a broad range of other immune cells), by blocking lymphocyte homing, increasing production of reactive oxygen and nitrogen species, promoting secretion of various cytokines, chemokines, and immune regulatory molecules, stimulation of other immunosuppressive cells, depletion of various metabolites, and upregulation of immune checkpoint molecules. Additionally, the heterogeneity of myeloid-derived suppressor cells in cancer makes their identification challenging. Overall, they serve as a major obstacle for many cancer immunotherapies and targeting them could be a favorable strategy to improve the effectiveness of immunotherapeutic interventions. However, in hematological malignancies, particularly B-cell malignancies, the clinical outcomes of targeting these myeloid-derived suppressor cells is a field that is still to be explored. This review summarizes the complex biology of myeloid-derived suppressor cells with an emphasis on the immunosuppressive pathways used by myeloid-derived suppressor cells to modulate T-cell function in hematological malignancies. In addition, we describe the challenges, therapeutic strategies, and clinical relevance of targeting myeloid-derived suppressor cells in these diseases.

Keywords:  hematological malignancies; immunosuppression; myeloid-derived suppressor cells; t cells; tumor microenvironment

DOI:  https://doi.org/10.3389/fcell.2023.1129343
Int J Mol Sci. 2023 Apr 14. pii: 7240. [Epub ahead of print]24(8):

Novel Therapeutic Targets for Tumor Microenvironment in Cancer.

Roberto Bei, Laura Masuelli.

The various immune effector cells that infiltrate the tumor microenvironment (TME) play a key role in directing the outcome of tumor growth [...].

DOI: https://doi.org/10.3390/ijms24087240
Anticancer Res. 2023 May;43(5): 1985-1992

TU-100 Antagonizes the M2 Polarization Phenotype of Macrophages in the Tumor Microenvironment by Suppressing the TLR4/NF-B/STAT3 Axis.

Shuhai Chen, Yuji Morine, Y U Saito, Shinichiro Yamada, Hiroki Teraoku, Tetsuya Ikemoto, Mitsuo Shimada.

   BACKGROUND/AIM: Macrophages are the most abundant immune cells in the tumor stroma, and their polarization states within the tumor microenvironment (TME) exert critical roles in tumorigenesis. TU-100 (Daikenchuto) is a commonly prescribed Japanese herbal medicine that has shown anti-cancer effects by regulating cancer-associated fibroblasts (CAFs) in the TME. However, its effects on tumor-associated macrophages (TAMs) remain unclear.
MATERIALS AND METHODS: TAMs were generated by macrophage exposure to tumor-conditioned medium (CM), and their polarization states were evaluated after TU-100 treatment. The underlying mechanism was further studied.
RESULTS: TU-100 exhibited little cytotoxicity over a range of doses in M0 macrophages and TAMs. However, it could antagonize the M2-like polarization of macrophages evoked by tumor-CM exposure. These effects might be caused by the inhibition of TLR4/NF-B/STAT3 signaling in the M2-like phenotype of macrophages. Interestingly, TU-100 antagonized the malignancy promoting effects of M2 macrophages on hepatocellular carcinoma cell lines in vitro. Mechanistically, the administration of TU-100 restrained the high expression of MMP-2, COX-2, and VEGF in TAMs.
CONCLUSION: TU-100 may alleviate the progression of cancer by regulating the M2 polarization of macrophages within the TME, suggesting a viable therapeutic approach.

Keywords:  M2 polarization; Toll-like receptor 4; Tumor-associated macrophages; nuclear factor-B; tumor microenvironment

DOI:  https://doi.org/10.21873/anticanres.16359
CNS Neurosci Ther. 2023 Apr 23.

Advances in research on immune escape mechanism of glioma.

Xu Guo, Gang Wang.

   BACKGROUND: Glioma is the most common primary intracranial malignancy in clinical practice, and in particular, IDH-wildtype glioblastoma has the worst prognosis. In recent years, surgical resection combined with simultaneous radiotherapy and immune checkpoint inhibitors has made some progress, but the efficacy is still not satisfactory, which may be related to the low immunogenicity of glioma cells and the tumor immunosuppressive microenvironment.
METHODS: A comprehensive review of relevant literature was conducted to explore the mechanisms by which tumors suppress antitumor immune responses and produce escape, with a focus on the immune cells in the tumor microenvironment (TME).
RESULTS: The mechanisms involved in immune evasion of glioma cells are complex and involve with immune cell differentiation and function.
CONCLUSION: Our review emphasizes the need for a more profound comprehension of the mechanisms involved in immune response and immune evasion in glioma, to formulate more efficacious treatment modalities.

Keywords:  glioblastoma; glioma; immune escape; immunotherapy; review; tumor microenvironment (TME)

DOI:  https://doi.org/10.1111/cns.14217
Cancer Res. 2023 Apr 28. pii: CAN-22-2220. [Epub ahead of print]

Tumor-derived Small Extracellular Vesicles Inhibit the Efficacy of CAR T Cells against Solid Tumors.

Wei Guo, Wenqun Zhong, Zebin Xiao, Zhiyuan Qin, Jingbo Yang, Yi Wen, Ziyan Yu, Yumei Li, Neil C Sheppard, Serge Y Fuchs, Xiaowei Xu, Meenhard Herlyn, Carl H June, Ellen Pure.

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in the treatment of hematologic malignancies. Unfortunately, it has limited efficacy against solid tumors, even when the targeted antigens are well expressed. A better understanding of the underlying mechanisms of CAR T cell therapy resistance in solid tumors is necessary to develop strategies to improve efficacy. Here we report that solid tumors release small extracellular vesicles (sEVs) that carry both targeted tumor antigens and the immune checkpoint protein PD-L1. These sEVs acted as cell-free functional units to preferentially interact with cognate CAR T cells and efficiently inhibited their proliferation, migration, and function. In syngeneic mouse tumor models, blocking tumor sEV secretion not only boosted the infiltration and anti-tumor activity of CAR T cells but also improved endogenous anti-tumor immunity. These results suggest that solid tumors use sEVs as an active defense mechanism to resist CAR T cells and implicate tumor sEVs as a potential therapeutic target to optimize CAR T cell therapy against solid tumors.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-2220
Front Oncol. 2023 ;13 1116016

Strategies to overcome myeloid cell induced immune suppression in the tumor microenvironment.

Jennifer Cao, Lyndah Chow, Steven Dow.

  Cancer progression and metastasis due to tumor immune evasion and drug resistance is strongly associated with immune suppressive cellular responses, particularly in the case of metastatic tumors. The myeloid cell component plays a key role within the tumor microenvironment (TME) and disrupts both adaptive and innate immune cell responses leading to loss of tumor control. Therefore, strategies to eliminate or modulate the myeloid cell compartment of the TME are increasingly attractive to non-specifically increase anti-tumoral immunity and enhance existing immunotherapies. This review covers current strategies targeting myeloid suppressor cells in the TME to enhance anti-tumoral immunity, including strategies that target chemokine receptors to deplete selected immune suppressive myeloid cells and relieve the inhibition imposed on the effector arms of adaptive immunity. Remodeling the TME can in turn improve the activity of other immunotherapies such as checkpoint blockade and adoptive T cell therapies in immunologically "cold" tumors. When possible, in this review, we have provided evidence and outcomes from recent or current clinical trials evaluating the effectiveness of the specific strategies used to target myeloid cells in the TME. The review seeks to provide a broad overview of how myeloid cell targeting can become a key foundational approach to an overall strategy for improving tumor responses to immunotherapy.

Keywords:  cancer; cancer immune therapy; dendritc cells; immune suppresion; myeloid derived suppressor cells (MDSC); tumor associate macrophages (TAM); tumor associated neutrophils (TAN); tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2023.1116016
Biochem Pharmacol. 2023 Apr 20. pii: S0006-2952(23)00156-9. [Epub ahead of print] 115565

Insights into the potential of Sanguinarine as a promising therapeutic option for breast cancer.

Rama Rao Malla, Priyamvada Bhamidipati, Meghapriya Adem.

  Breast cancer (BC) is one of the leading causes of cancer-related deaths in women worldwide. The tumor microenvironment (TME) plays a crucial role in the progression and metastasis of BC. A significant proportion of BC is characterized by a hypoxic TME, which contributes to the development of drug resistance and cancer recurrence. Sanguinarine (SAN), an isoquinoline alkaloid found in Papaver plants, has shown promise as an anticancer agent. The present review focuses on exploring the molecular mechanisms of hypoxic TME in BC and the potential of SAN as a therapeutic option. The review presents the current understanding of the hypoxic TME, its signaling pathways, and its impact on the progression of BC. Additionally, the review elaborates on the mechanisms of action of SAN in BC, including its effects on vital cellular processes such as proliferation, migration, drug resistance, and tumor-induced immune suppression. The review highlights the importance of addressing hypoxic TME in treating BC and the potential of SAN as a promising therapeutic option.

Keywords:  Breast cancer; hypoxia; prognosis; sanguinarine; tumor microenvironment

DOI:  https://doi.org/10.1016/j.bcp.2023.115565
J Exp Med. 2023 Jun 05. pii: e20230600. [Epub ahead of print]220(6):

Ruth Scherz-Shouval: Together we can ask big questions.

Lucie Van Emmenis.

Ruth Scherz-Shouval is an Assistant Professor in the Department of Biomolecular Sciences at the Weizmann Institute of Science, Israel. Her lab is interested in the tumor microenvironment, how stress responses can shape the tumor microenvironment, and also how different cells within the tumor microenvironment interact. We talked about how her interest in science began at an early age, the impact of having strong female role models, and ways to encourage collaboration and create an engaging and welcoming lab environment.

DOI: https://doi.org/10.1084/jem.20230600
Front Immunol. 2023 ;14 1176807

Tumor-associated macrophages: Prognostic and therapeutic targets for cancer in humans and dogs.

Rachel V Brady, Douglas H Thamm.

  Macrophages are ancient, phagocytic immune cells thought to have their origins 500 million years ago in metazoan phylogeny. The understanding of macrophages has evolved to encompass their foundational roles in development, homeostasis, tissue repair, inflammation, and immunity. Notably, macrophages display high plasticity in response to environmental cues, capable of a strikingly wide variety of dynamic gene signatures and phenotypes. Macrophages are also involved in many pathological states including neural disease, asthma, liver disease, heart disease, cancer, and others. In cancer, most tumor-associated immune cells are macrophages, coined tumor-associated macrophages (TAMs). While some TAMs can display anti-tumor properties such as phagocytizing tumor cells and orchestrating an immune response, most macrophages in the tumor microenvironment are immunosuppressive and pro-tumorigenic. Macrophages have been implicated in all stages of cancer. Therefore, interest in manipulating macrophages as a therapeutic strategy against cancer developed as early as the 1970s. Companion dogs are a strong comparative immuno-oncology model for people due to documented similarities in the immune system and spontaneous cancers between the species. Data from clinical trials in humans and dogs can be leveraged to further scientific advancements that benefit both species. This review aims to provide a summary of the current state of knowledge on macrophages in general, and an in-depth review of macrophages as a therapeutic strategy against cancer in humans and companion dogs.

Keywords:  cancer; dog (canine); immunotherapy; oncology; tumor microenvironment; tumor-associated macrophage

DOI:  https://doi.org/10.3389/fimmu.2023.1176807
Adv Exp Med Biol. 2023 ;1408 309-328

Transforming Growth Factor-β1 in Cancer Immunology: Opportunities for Immunotherapy.

Víctor H Villar, Tijana Subotički, Dragoslava Đikić, Olivera Mitrović-Ajtić, Felipe Simon, Juan F Santibanez.

  Transforming growth factor-beta1 (TGF-β) regulates a plethora of cell-intrinsic processes that modulate tumor progression in a context-dependent manner. Thus, although TGF-β acts as a tumor suppressor in the early stages of tumorigenesis, in late stages, this factor promotes tumor progression and metastasis. In addition, TGF-β also impinges on the tumor microenvironment by modulating the immune system. In this aspect, TGF-β exhibits a potent immunosuppressive effect, which allows both cancer cells to escape from immune surveillance and confers resistance to immunotherapy. While TGF-β inhibits the activation and antitumoral functions of T-cell lymphocytes, dendritic cells, and natural killer cells, it promotes the generation of T-regulatory cells and myeloid-derived suppressor cells, which hinder antitumoral T-cell activities. Moreover, TGF-β promotes tumor-associated macrophages and neutrophils polarization from M1 into M2 and N1 to N2, respectively. Altogether, these effects contribute to the generation of an immunosuppressive tumor microenvironment and support tumor promotion. This review aims to analyze the relevant evidence on the complex role of TGF-β in cancer immunology, the current outcomes of combined immunotherapies, and the anti-TGF-β therapies that may improve the success of current and new oncotherapies.

Keywords:  Cancer; Immunosuppression; Immunotherapy; T-cell lymphocyte; TGF-β1

DOI:  https://doi.org/10.1007/978-3-031-26163-3_17
Biomed Pharmacother. 2023 Apr 25. pii: S0753-3322(23)00559-0. [Epub ahead of print]163 114770

Dual antitumor immunomodulatory effects of PARP inhibitor on the tumor microenvironment: A counterbalance between anti-tumor and pro-tumor.

Xiao-Fang Yi, Ruo-Lin Gao, Li Sun, Zhi-Xuan Wu, Shu-Ling Zhang, Le-Tian Huang, Cheng-Bo Han, Jie-Tao Ma.

  Poly (ADP-ribose)-polymerases (PARPs) play an essential role in the maintenance of genome integrity, DNA repair, and apoptosis. PARP inhibitors (PARPi) exert antitumor effects via synthetic lethality and PARP trapping. PARPi impact the antitumor immune response by modulating the tumor microenvironment, and their effect has dual properties of promoting and inhibiting the antitumor immune response. PARPi promote M1 macrophage polarization, antigen presentation by dendritic cells, infiltration of B and T cells and their killing capacity and inhibit tumor angiogenesis. PARPi can also inhibit the activation and function of immune cells by upregulating PD-L1. In this review, we summarize the dual immunomodulatory effects and possible underlying mechanisms of PARPi, providing a basis for the design of combination regimens for clinical treatment and the identification of populations who may benefit from these therapies.

Keywords:  Angiogenesis; Immune cells; PARP inhibitor; PD-L1; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.biopha.2023.114770
Int J Mol Sci. 2023 Apr 19. pii: 7493. [Epub ahead of print]24(8):

Tumor-Associated Macrophage Subsets: Shaping Polarization and Targeting.

Qindong Zhang, Mouldy Sioud.

  The tumor microenvironment (TME) is a critical regulator of tumor growth, progression, and metastasis. Among the innate immune cells recruited to the tumor site, macrophages are the most abundant cell population and are present at all stages of tumor progression. They undergo M1/M2 polarization in response to signals derived from TME. M1 macrophages suppress tumor growth, while their M2 counterparts exert pro-tumoral effects by promoting tumor growth, angiogenesis, metastasis, and resistance to current therapies. Several subsets of the M2 phenotype have been observed, often denoted as M2a, M2b, M2c, and M2d. These are induced by different stimuli and differ in phenotypes as well as functions. In this review, we discuss the key features of each M2 subset, their implications in cancers, and highlight the strategies that are being developed to harness TAMs for cancer treatment.

Keywords:  cell signaling; polarization; solid cancers; targeted therapy; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3390/ijms24087493
Pharmaceutics. 2023 Apr 04. pii: 1143. [Epub ahead of print]15(4):

Cancer Resistance to Immunotherapy: Comprehensive Insights with Future Perspectives.

Sawsan Sudqi Said, Wisam Nabeel Ibrahim.

  Cancer immunotherapy is a type of treatment that harnesses the power of the immune systems of patients to target cancer cells with better precision compared to traditional chemotherapy. Several lines of treatment have been approved by the US Food and Drug Administration (FDA) and have led to remarkable success in the treatment of solid tumors, such as melanoma and small-cell lung cancer. These immunotherapies include checkpoint inhibitors, cytokines, and vaccines, while the chimeric antigen receptor (CAR) T-cell treatment has shown better responses in hematological malignancies. Despite these breakthrough achievements, the response to treatment has been variable among patients, and only a small percentage of cancer patients gained from this treatment, depending on the histological type of tumor and other host factors. Cancer cells develop mechanisms to avoid interacting with immune cells in these circumstances, which has an adverse effect on how effectively they react to therapy. These mechanisms arise either due to intrinsic factors within cancer cells or due other cells within the tumor microenvironment (TME). When this scenario is used in a therapeutic setting, the term "resistance to immunotherapy" is applied; "primary resistance" denotes a failure to respond to treatment from the start, and "secondary resistance" denotes a relapse following the initial response to immunotherapy. Here, we provide a thorough summary of the internal and external mechanisms underlying tumor resistance to immunotherapy. Furthermore, a variety of immunotherapies are briefly discussed, along with recent developments that have been employed to prevent relapses following treatment, with a focus on upcoming initiatives to improve the efficacy of immunotherapy for cancer patients.

Keywords:  cancer immunotherapy; immune checkpoint inhibitors; resistance; tumor microenvironment

DOI:  https://doi.org/10.3390/pharmaceutics15041143
Front Oncol. 2023 ;13 1166676

Editorial: The interconnection between epigenetic modifications and the tumor microenvironment.

Siyuan He, Feng Jiang.



Keywords:  cancer biomarkers; epigenetic modification; immunotherapy; oncology; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2023.1166676
J Immunol Regen Med. 2023 May;pii: 100074. [Epub ahead of print]20

Engineered anti-prostate cancer CAR-neutrophils from human pluripotent stem cells.

Jackson D Harris, Yun Chang, Ramizah Syahirah, Xiaojun Lance Lian, Qing Deng, Xiaoping Bao.

  Immunotherapy is a powerful technique where immune cells are modified to improve cytotoxicity against cancerous cells to treat cancers that do not respond to surgery, chemotherapy, or radiotherapy. Expressing chimeric antigen receptor (CAR) in immune cells, typically T lymphocytes, is a practical modification that drives an immune response against cancerous tissue. CAR-T efficacy is suboptimal in solid tumors due to the tumor microenvironment (TME) that limits T lymphocyte cytotoxicity. In this study, we demonstrate that neutrophils differentiated from human pluripotent stem cells modified with AAVS1-inserted CAR constructs showed a robust cytotoxic effect against prostate-specific membrane antigen (PSMA) expressing LNCaP cells as a model for prostate cancer in vitro. Our results suggest that engineered CAR can significantly enhance the neutrophil anti-tumor effect, providing a new avenue in treating prostate cancers.

Keywords:  Cancer immunotherapy; Chimeric antigen receptor; Human pluripotent stem cells; Neutrophils

DOI:  https://doi.org/10.1016/j.regen.2023.100074
Int J Mol Sci. 2023 Apr 08. pii: 6945. [Epub ahead of print]24(8):

Therapeutic Potential of Tumor Metabolic Reprogramming in Triple-Negative Breast Cancer.

Gyöngyi Munkácsy, Libero Santarpia, Balázs Győrffy.

  Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with clinical features of high metastatic potential, susceptibility to relapse, and poor prognosis. TNBC lacks the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It is characterized by genomic and transcriptional heterogeneity and a tumor microenvironment (TME) with the presence of high levels of stromal tumor-infiltrating lymphocytes (TILs), immunogenicity, and an important immunosuppressive landscape. Recent evidence suggests that metabolic changes in the TME play a key role in molding tumor development by impacting the stromal and immune cell fractions, TME composition, and activation. Hence, a complex inter-talk between metabolic and TME signaling in TNBC exists, highlighting the possibility of uncovering and investigating novel therapeutic targets. A better understanding of the interaction between the TME and tumor cells, and the underlying molecular mechanisms of cell-cell communication signaling, may uncover additional targets for better therapeutic strategies in TNBC treatment. In this review, we aim to discuss the mechanisms in tumor metabolic reprogramming, linking these changes to potential targetable molecular mechanisms to generate new, physical science-inspired clinical translational insights for the cure of TNBC.

Keywords:  cancer metabolism; reprogramming; signaling pathway; therapeutic signaling; triple-negative breast cancer; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms24086945
J Immunother Cancer. 2023 Apr;pii: e006434. [Epub ahead of print]11(4):

Harnessing novel strategies and cell types to overcome immune tolerance during adoptive cell therapy in cancer.

Shi Yong Neo, Shengli Xu, Joni Chong, Kong-Peng Lam, Jing Wu.

  Cell therapy encompasses an expanding spectrum of cell-based regimes for the treatment of human ailments, such as the use of immune cells, in particular T cells, for combating tumors and the modulation of inflammatory immune responses. In this review, we focus on cell therapy in the immuno-oncology space, which is largely driven by interests and demands from the clinics for better solutions to target various hard-to-treat cancers. We discuss recent advances in various types of cell therapies, including T cell receptor-T cells, chimeric antigen receptor (CAR)-T cells, tumor-infiltrating lymphocytes and natural killer cells. Particularly, the present review focuses on the strategies to improve therapeutic responses by either enhancing tumor recognition or the resilience of infused immune cells within tumor microenvironment. Finally, we discuss the potential of other innate or innate-like immune cell types currently being explored as promising CAR-cell alternatives that seek to address the limitations of conventional adoptive cell therapies.

Keywords:  adoptive; cell engineering; chimeric antigen; immunotherapy; killer cells; lymphocytes; natural; receptors; tumor-infiltrating

DOI:  https://doi.org/10.1136/jitc-2022-006434
Cancer Lett. 2023 Apr 23. pii: S0304-3835(23)00144-1. [Epub ahead of print]563 216193

Tumor-host colluding through erythroid progenitor cells: Mechanisms and opportunities.

Yuan-Yuan Wang, Zhi-Zhong Wu, Cong-Fa Huang, Zhi-Jun Sun.

  Immunotherapy, particularly immune checkpoint blockade (ICB), has shown great promise in the treatment of cancer and emerged as a beacon of hope for patients who have exhausted traditional therapeutic options. Despite ICB's approval for the treatment of advanced tumors, its efficacy remains limited to a small subset of patients. As a systemic disease, cancer can induce changes in the composition and function of the systemic immune system, and ICB resistance often involves a dialog between the tumor microenvironment (TME) and the systemic immune macroenvironment. While investigations into tumor progression and ICB resistance have largely focused on the TME itself, the alterations in the systemic immune system and immune macroenvironment are still poorly understood. Given the spleen's role as the largest secondary lymphoid organ, its examination and discussion may provide valuable insights into the systemic immune status and TME components. Recent studies have highlighted the importance of the spleen in tumor progression and immunotherapy, particularly in the context of erythroid progenitor cells (EPCs), a significant cell subpopulation. In this review, we discuss the mechanisms and role of splenic extramedullary hematopoiesis (EMH) as an intermediary in tumor-host interactions and explore the mechanism of EPC-TME collusions. We further summarize the progress in EPC-targeting strategies and emphasize the potential for further research into the role and mechanisms of EPCs in tumor progression and treatment, which could have far-reaching implications.

Keywords:  Extramedullary hematopoiesis; Immune evasion; Immune macroenvironment; Spleen; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2023.216193
Med Res Rev. 2023 Apr 27.

The tumor microenvironment in the postsurgical liver: Mechanisms and potential targets of postoperative recurrence in human hepatocellular carcinoma.

Junyu Wu, Yau-Tuen Chan, Yuanjun Lu, Ning Wang, Yibin Feng.

  Surgery remains to be the mainstay of treatment for hepatocellular carcinoma (HCC). Nonetheless, its therapeutic efficacy is significantly impaired by postoperative recurrence, which occurs in more than half of cases as a result of intrahepatic metastasis or de novo tumorigenesis. For decades, most therapeutic strategies on inhibiting postoperative HCC recurrence have been focused on the residual tumor cells but satisfying therapeutic outcomes are barely observed in the clinic. In recent years, a better understanding of tumor biology allows us to shift our focus from tumor cells toward the postoperative tumor microenvironment (TME), which is gradually identified to play a pivotal role in tumor recurrence. In this review, we describe various surgical stress and surgical perturbation on postoperative TME. Besides, we discuss how such alternations in TME give rise to postoperative recurrence of HCC. Based on its clinical significance, we additionally highlight the potential of the postoperative TME as a target for postoperative adjuvant therapeutics.

Keywords:  HCC recurrence; mechanism; postoperative recurrence; surgical stress; tumor microenvironment

DOI:  https://doi.org/10.1002/med.21967
bioRxiv. 2023 Apr 13. pii: 2023.04.12.536619. [Epub ahead of print]

Carcinoma-associated fibroblast-like tumor cells remodel the Ewing sarcoma tumor microenvironment.

Emma D Wrenn, April A Apfelbaum, Erin R Rudzinski, Xuemei Deng, Wei Jiang, Sudha Sud, Raelene A Van Noord, Erika A Newman, Nicolas M Garcia, Virginia J Hoglund, Shruti S Bhise, Sami B Kanaan, Olivia G Waltner, Scott N Furlan, Elizabeth R Lawlor.

Tumor heterogeneity is a major driver of cancer progression. In epithelial-derived malignancies, carcinoma-associated fibroblasts (CAFs) contribute to tumor heterogeneity by depositing extracellular matrix (ECM) proteins that dynamically remodel the tumor microenvironment (TME). Ewing sarcomas (EwS) are histologically monomorphous, mesenchyme-derived tumors that are devoid of CAFs. Here we identify a previously uncharacterized subpopulation of transcriptionally distinct EwS tumor cells that deposit pro-tumorigenic ECM. Single cell analyses revealed that these CAF-like cells differ from bulk EwS cells by their upregulation of a matrisome-rich gene signature that is normally repressed by EWS::FLI1, the oncogenic fusion transcription factor that underlies EwS pathogenesis. Further, our studies showed that ECM-depositing tumor cells express the cell surface marker CD73, allowing for their isolation ex vivo and detection in situ. Spatial profiling of tumor xenografts and patient biopsies demonstrated that CD73 + EwS cells and tumor cell-derived ECM are prevalent along tumor borders and invasive fronts. Importantly, despite loss of EWS::FLI1-mediated gene repression, CD73 + EwS cells retain expression of EWS::FLI1 and the fusion-activated gene signature, as well as tumorigenic and proliferative capacities. Thus, EwS tumor cells can be reprogrammed to adopt CAF-like properties and these transcriptionally and phenotypically distinct cell subpopulations contribute to tumor heterogeneity by remodeling the TME.

DOI: https://doi.org/10.1101/2023.04.12.536619
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2023 Apr;31(2): 589-592

[Research Progress on the Role of Tumor-Associated Macrophages in Multiple Myeloma --Review].

Ping-Ping Zhang, Bing-Zong Li, Ying-Hua Geng, Feng Zhang, Yan-Li Yang.

  Bone marrow microenvironment is a highly complex environment surrounding tumor, which plays an important role in the survival, proliferation, drug resistance and migration of multiple myeloma (MM) cells. As an important cellular component in tumor microenvironment, tumor-associated macrophages(TAM) has attracted attention due to its key role in tumor progression and drug resistance. Targeting TAM has shown potential therapeutic value in cancer treatment. In order to clarify the role of macrophages in MM progression, it is necessary to understand the differentiation of TAM and its characteristics of promoting MM. This paper reviews the research progress on how TAM is programmed in MM and the mechanism of TAM promoting tumor development and drug resistance.

Keywords:   immunosuppression ; angiogenesis ; drug resistance ; multiple myeloma ; tumor-associated macrophages

DOI:  https://doi.org/10.19746/j.cnki.issn.1009-2137.2023.02.041
Oncotarget. 2023 Apr 24. 14 364-365

The critical immune basis for differential responses to immunotherapy in primary versus metastatic pancreatic cancer.

Brian Diskin, Sarah Schwartz, George Miller.



Keywords:  immunnotherapy; liver metastasis; pancreatic cancer

DOI:  https://doi.org/10.18632/oncotarget.28373
Acta Pharmacol Sin. 2023 Apr 24.

COPS6 promotes tumor progression and reduces CD8+ T cell infiltration by repressing IL-6 production to facilitate tumor immune evasion in breast cancer.

Wen-Qi Du, Zhi-Man Zhu, Xin Jiang, Meng-Jie Kang, Dong-Sheng Pei.

  Due to poor T cell infiltration, tumors evade immune surveillance. Increased CD8+ T cell infiltration in breast cancer suggests a satisfactory response to immunotherapy. COPS6 has been identified as an oncogene, but its role in regulating antitumor immune responses has not been defined. In this study, we investigated the impact of COPS6 on tumor immune evasion in vivo. Tumor transplantation models were established in C57BL/6 J mice and BALB/c nude mice. Flow cytometry was conducted to identify the role of COPS6 on tumor-infiltrating CD8+ T cells. By analyzing the TCGA and GTEx cohort, we found that COPS6 expression was significantly up-regulated in a variety of cancers. In human osteosarcoma cell line U2OS and non-small cell lung cancer cell line H1299, we showed that p53 negatively regulated COPS6 promoter activity. In human breast cancer MCF-7 cells, COPS6 overexpression stimulated p-AKT expression as well as the proliferation and malignant transformation of tumor cells, whereas knockdown of COPS6 caused opposite effects. Knockdown of COPS6 also significantly suppressed the growth of mouse mammary cancer EMT6 xenografts in BALB/c nude mice. Bioinformatics analysis suggested that COPS6 was a mediator of IL-6 production in the tumor microenvironment and a negative regulator of CD8+ T cell tumor infiltration in breast cancer. In C57BL6 mice bearing EMT6 xenografts, COPS6 knockdown in the EMT6 cells increased the number of tumor-infiltrating CD8+ T cells, while knockdown of IL-6 in COPS6KD EMT6 cells diminished tumor infiltrating CD8+ T cells. We conclude that COPS6 promotes breast cancer progression by reducing CD8+ T cell infiltration and function via the regulation of IL-6 secretion. This study clarifies the role of p53/COPS6/IL-6/CD8+ tumor infiltrating lymphocytes signaling in breast cancer progression and immune evasion, opening a new path for development of COPS6-targeting therapies to enhance tumor immunogenicity and treat immunologically "cold" breast cancer.

Keywords:  COPS6; IL-6; breast cancer; immunotherapy; p53; tumor immune evasion

DOI:  https://doi.org/10.1038/s41401-023-01085-8
Life (Basel). 2023 Apr 19. pii: 1050. [Epub ahead of print]13(4):

TIGIT in Lung Cancer: Potential Theranostic Implications.

Carlo Pescia, Giuditta Pini, Edoardo Olmeda, Stefano Ferrero, Gianluca Lopez.

  TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a co-inhibitory receptor expressed on various immune cells, including T cells, NK cells, and dendritic cells. TIGIT interacts with different ligands, such as CD155 and CD112, which are highly expressed on cancer cells, leading to the suppression of immune responses. Recent studies have highlighted the importance of TIGIT in regulating immune cell function in the tumor microenvironment and its role as a potential therapeutic target, especially in the field of lung cancer. However, the role of TIGIT in cancer development and progression remains controversial, particularly regarding the relevance of its expression both in the tumor microenvironment and on tumor cells, with prognostic and predictive implications that remain to date essentially undisclosed. Here, we provide a review of the recent advances in TIGIT-blockade in lung cancer, and also insights on TIGIT relevance as an immunohistochemical biomarker and its possible theranostic implications.

Keywords:  PD-1; PD-L1; TIGIT; immune-checkpoint; lung cancer; predictive; prognostic; theranostic

DOI:  https://doi.org/10.3390/life13041050
Medicina (Kaunas). 2023 Apr 07. pii: 728. [Epub ahead of print]59(4):

Infiltration by Intratumor and Stromal CD8 and CD68 in Cervical Cancer.

Polina Dimitrova, Mariela Vasileva-Slaveva, Velizar Shivarov, Ihsan Hasan, Angel Yordanov.

  Background and Objectives: The tumor microenvironment (TME) plays a major role in neoplastic development. Various types of cells can be found in the TME. These cells can be classified into two groups, immunosuppressive and immunostimulatory types, depending on the function they perform in the antitumor immune response (IR). By interacting both with each other and with tumor cells, different immune mechanisms are activated or inhibited, which can suppress or promote the development and progression of cervical cancer (CC). Our aim was to investigate some of the main components of the cellular immune response in TME-tumor-infiltrating cytotoxic T cells (Tc, CD8+) and tumor-associated macrophages (TAMs, CD68+)-in patients with CC. Materials and Methods: We analyzed 72 paraffin-embedded tumor tissues of patients diagnosed and treated at Medical University Pleven, Bulgaria. Patients were classified according to the 2018 FIGO (International Federation of Gynaecology and Obstetrics) classification. From each patient, we selected one histological slide with hematoxylin eosin staining. In a microscopic evaluation, CD8+ T lymphocytes and CD68+-positive macrophages were counted in the tumor and stroma of five randomly selected fields at ×40 magnification (HPF). We analyzed the relationship between intratumoral and stromal CD8 and CD68 expression and FIGO stage and N status. Results: There was no significant association between the expression levels of intratumoral and stromal CD68+ cells in the different FIGO stages and according to the lymph nodes' involvement. For CD8+ cells, the association of stromal infiltration was also not found, but T intratumor infiltration was associated with a higher FIGO stage, despite the fact that the results did not reach significance (p = 0.063, Fisher test). Intratumoral CD8+ cells were significantly associated with positive N status, (p = 0.035). Discussion: The separation of tumor-infiltrating cytotoxic T cells and tumor-associated macrophages into intratumoral and stromal is inconsequential. In our study, the level of infiltration of CD68+ cells in tumors and stromata was not significantly associated with tumor progression or lymph node involvement. The results were different for CD8+ cells, in which levels of infiltration were associated with lymph nodes' statuses. Conclusions: The separate evaluation of CD68+ immune cells in the TME as intratumoral and stromal is not beneficial for defining prognoses, since the presence of these cells is not associated with the patient's stage. In our study, the presence of CD8+ cells was significantly associated with lymph node metastases. The prognostic value of the obtained results can be enriched with an additional study of the lymphocyte phenotype, including B and other subtypes of T lymphocytes, NK cells, as well as molecules involved in the immune response, such as HLA subtypes.

Keywords:  CD68; CD8; cervical cancer; intratumoral; stromal

DOI:  https://doi.org/10.3390/medicina59040728
Breast Cancer. 2023 Apr 27.

Correction: Programmed death ligand 1-positive immune cells in primary tumor or metastatic axillary lymph nodes can predict prognosis of triple-negative breast cancer even when present at < 1% in the tumor region.

Nobumoto Tomioka, Kanako C Hatanaka, Dai Okuyama, Ken-Ichi Watanabe, Mitsugu Yamamoto, Hideki Maeda, Hanae Tachikawa, Sayuri Kuwahara, Ai Shimizu, Hiroaki Suzuki, Yutaka Hatanaka, Masato Takahashi.

DOI: https://doi.org/10.1007/s12282-023-01454-5
Trends Cancer. 2023 Apr 26. pii: S2405-8033(23)00058-4. [Epub ahead of print]

Immune mechanisms of toxicity from checkpoint inhibitors.

S Jennifer Wang, Stephanie K Dougan, Michael Dougan.

  Immunotherapy has changed the treatment landscape for cancer over the past decade. Inhibitors of the immune checkpoint proteins cytotoxic T lymphocyte antigen (CTLA)-4, programmed death (PD)-1, and PD ligand 1 (PD-L1) can induce durable remissions in a subset of patients with metastatic disease. However, these treatments can be limited by inflammatory toxicities that can affect any organ system in the body and in some cases can be life threatening. Considerable progress has been made in understanding the drivers of these toxicities as well as effective management strategies. Further research into understanding the molecular and cellular mechanisms that drive toxicity will enable better prediction of toxicity and development of optimized therapies for these toxicities that avoid interfering with antitumor immunity. In this review, we discuss our current understanding of the inflammatory toxicities from immune checkpoint inhibitors (ICIs) and propose optimal treatment strategies for these toxicities.

Keywords:  cancer immunotherapy; checkpoint blockade; immune checkpoint inhibitor; immune-related adverse events; inflammatory toxicity

DOI:  https://doi.org/10.1016/j.trecan.2023.04.002
Front Bioeng Biotechnol. 2023 ;11 1150764

Key aspects for conception and construction of co-culture models of tumor-stroma interactions.

James Mason, Daniel Öhlund.

  The tumor microenvironment is crucial in the initiation and progression of cancers. The interplay between cancer cells and the surrounding stroma shapes the tumor biology and dictates the response to cancer therapies. Consequently, a better understanding of the interactions between cancer cells and different components of the tumor microenvironment will drive progress in developing novel, effective, treatment strategies. Co-cultures can be used to study various aspects of these interactions in detail. This includes studies of paracrine relationships between cancer cells and stromal cells such as fibroblasts, endothelial cells, and immune cells, as well as the influence of physical and mechanical interactions with the extracellular matrix of the tumor microenvironment. The development of novel co-culture models to study the tumor microenvironment has progressed rapidly over recent years. Many of these models have already been shown to be powerful tools for further understanding of the pathophysiological role of the stroma and provide mechanistic insights into tumor-stromal interactions. Here we give a structured overview of different co-culture models that have been established to study tumor-stromal interactions and what we have learnt from these models. We also introduce a set of guidelines for generating and reporting co-culture experiments to facilitate experimental robustness and reproducibility.

Keywords:  cancer associated fibroblasts; cell culture models; co-culture; organoid; tumor-stroma interactions

DOI:  https://doi.org/10.3389/fbioe.2023.1150764
J Clin Invest. 2023 May 01. pii: e164528. [Epub ahead of print]133(9):

Targeting fibrinogen-like protein 1 enhances immunotherapy in hepatocellular carcinoma.

Mingen Lin, Jing He, Xinchao Zhang, Xue Sun, Wenjing Dong, Ruonan Zhang, Yanping Xu, Lei Lv.

  How cancer cells evade the therapeutic effects of immune checkpoint blockade is largely unknown. Here, we report that fibrinogen-like protein 1 (FGL1), a newly identified immune checkpoint ligand, was modified by acetylation at Lys 98 in hepatocellular carcinoma (HCC), which targeted it for proteasomal degradation. Sirtuin 2 (SIRT2) deacetylated and stabilized FGL1, thus promoting immune evasion. Notably, the SIRT2 inhibitor 2-Cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide (AGK2) enhanced acetylation of FGL1 and reduced FGL1 protein levels in vitro. The combination of AGK2 and programmed death ligand 1 (PD-L1) blockade effectively suppressed tumor growth and improved overall survival of mice. Furthermore, aspirin, an old drug, could directly acetylate FGL1 at Lys 98 and promote its degradation in vitro. Aspirin enhanced the immunotherapeutic efficacy, induced tumor regression, and extended the lifespan of tumor-bearing mice. Furthermore, the SIRT2/FGL1 axis was expressed in HCC specimens. Collectively, these findings unveil an acetylation-mediated regulation of FGL1, identify a potential target for HCC immunotherapy, and provide therapeutic strategies for the clinical treatment of HCC.

Keywords:  Cancer immunotherapy; Cell Biology; Immunology; Immunotherapy; Liver cancer

DOI:  https://doi.org/10.1172/JCI164528
Adv Sci (Weinh). 2023 Apr 24. e2206889

IL-1β Is an Androgen-Responsive Target in Macrophages for Immunotherapy of Prostate Cancer.

Deng Wang, Chaping Cheng, Xinyu Chen, Jinming Wang, Kaiyuan Liu, Na Jing, Penghui Xu, Xialian Xi, Yujiao Sun, Zhongzhong Ji, Huifang Zhao, Yuman He, Kai Zhang, Xinxing Du, Baijun Dong, Yuxiang Fang, Pengcheng Zhang, Xueming Qian, Wei Xue, Wei-Qiang Gao, Helen He Zhu.

  Great attention is paid to the role of androgen receptor (AR) as a central transcriptional factor in driving the growth of prostate cancer (PCa) epithelial cells. However, the understanding of the role of androgen in PCa-infiltrated immune cells and the impact of androgen deprivation therapy (ADT), the first-line treatment for advanced PCa, on the PCa immune microenvironment remains limited. On the other hand, immune checkpoint blockade has revolutionized the treatment of certain cancer types, but fails to achieve any benefit in advanced PCa, due to an immune suppressive environment. In this study, it is reported that AR signaling pathway is evidently activated in tumor-associated macrophages (TAMs) of PCa both in mice and humans. AR acts as a transcriptional repressor for IL1B in TAMs. ADT releases the restraint of AR on IL1B and therefore leads to an excessive expression and secretion of IL-1β in TAMs. IL-1β induces myeloid-derived suppressor cells (MDSCs) accumulation that inhibits the activation of cytotoxic T cells, leading to the immune suppressive microenvironment. Critically, anti-IL-1β antibody coupled with ADT and the immune checkpoint inhibitor anti-PD-1 antibody exerts a stronger anticancer effect on PCa following castration. Together, IL-1β is an important androgen-responsive immunotherapeutic target for advanced PCa.

Keywords:  IL-1β; androgen deprivation therapy; androgen receptor; immune therapy; prostate cancer; tumor-associated macrophage

DOI:  https://doi.org/10.1002/advs.202206889
Biomed Pharmacother. 2023 Apr 24. pii: S0753-3322(23)00551-6. [Epub ahead of print]163 114762

The "Self-eating" of cancer-associated fibroblast: A potential target for cancer.

Yan Chen, Xiaozhen Zhang, Hanshen Yang, Tingbo Liang, Xueli Bai.

  Autophagy helps maintain energy homeostasis and protect cells from stress effects by selectively removing misfolded/polyubiquitylated proteins, lipids, and damaged mitochondria. Cancer-associated fibroblasts (CAFs) are cellular components of tumor microenvironment (TME). Autophagy in CAFs inhibits tumor development in the early stages; however, it has a tumor-promoting effect in advanced stages. In this review, we aimed to summarize the modulators responsible for the induction of autophagy in CAFs, such as hypoxia, nutrient deprivation, mitochondrial stress, and endoplasmic reticulum stress. In addition, we aimed to present autophagy-related signaling pathways in CAFs, and role of autophagy in CAF activation, tumor progression, tumor immune microenvironment. Autophagy in CAFs may be an emerging target for tumor therapy. In summary, autophagy in CAFs is regulated by a variety of modulators and can reshape tumor immune microenvironment, affecting tumor progression and treatment.

Keywords:  Autophagy; Cancer; Cancer therapy; Cancer-associated fibroblast; Tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.biopha.2023.114762
Proc Natl Acad Sci U S A. 2023 May 02. 120(18): e2216587120

Programmed cell death-1 receptor-mediated regulation of Tbet+NK1.1- innate lymphoid cells within the tumor microenvironment.

Jing Xuan Lim, Chester Y Lai, Grace E Mallett, David McDonald, Gillian Hulme, Stephanie Laba, Andrew Shapanis, Megan Payne, Warren Patterson, Michael Alexander, Jonathan Coxhead, Andrew Filby, Ruth Plummer, Penny E Lovat, Giuseppe Sciume, Eugene Healy, Shoba Amarnath.

  Innate lymphoid cells (ILCs) play a key role in tissue-mediated immunity and can be controlled by coreceptor signaling. Here, we define a subset of ILCs that are Tbet+NK1.1- and are present within the tumor microenvironment (TME). We show programmed death-1 receptor (PD-1) expression on ILCs within TME is found in Tbet+NK1.1- ILCs. PD-1 significantly controlled the proliferation and function of Tbet+NK1.1- ILCs in multiple murine and human tumors. We found tumor-derived lactate enhanced PD-1 expression on Tbet+NK1.1- ILCs within the TME, which resulted in dampened the mammalian target of rapamycin (mTOR) signaling along with increased fatty acid uptake. In line with these metabolic changes, PD-1-deficient Tbet+NK1.1- ILCs expressed significantly increased IFNγ and granzyme B and K. Furthermore, PD-1-deficient Tbet+NK1.1- ILCs contributed toward diminished tumor growth in an experimental murine model of melanoma. These data demonstrate that PD-1 can regulate antitumor responses of Tbet+NK1.1- ILCs within the TME.

Keywords:  ILC; PD-1; cSCC; melanoma

DOI:  https://doi.org/10.1073/pnas.2216587120
Antioxidants (Basel). 2023 Mar 27. pii: 813. [Epub ahead of print]12(4):

TNF-Alpha Promotes an Inflammatory Mammary Microenvironment That Favors Macrophage and Epithelial Migration in a CCL2- and Mitochondrial-ROS-Dependent Manner.

María Jesús Vera, Francisco Guajardo, Felix A Urra, Nicolás Tobar, Jorge Martínez.

  The influence of an inflammatory microenvironment on tumorigenesis has been widely accepted. Systemic conditions that favor the onset of an inflammatory landscape predispose the progression of breast cancer. Under obesity conditions, the endocrine function of adipose tissue is one of the main determinants of the production of local and systemic inflammatory mediators. Although these mediators can stimulate tumorigenesis and recruit inflammatory cells, as macrophages, the mechanism involved remains poorly understood. In the present work, we describe that the TNFα treatment of mammary preadipocytes from human normal patients blocks adipose differentiation and promotes the generation of pro-inflammatory soluble factors. The latter stimulate the mobilization of THP-1 monocytes and MCF-7 epithelial cancer cells in an MCP1/CCL2- and mitochondrial-ROS-dependent manner. Together, these results reaffirm the contribution of an inflammatory microenvironment and mtROS in the progression of breast cancer.

Keywords:  OXPHOS; adipocytes; breast cancer; migration; monocytes

DOI:  https://doi.org/10.3390/antiox12040813
Int J Mol Sci. 2023 Apr 15. pii: 7317. [Epub ahead of print]24(8):

The Diet as a Modulator of Tumor Microenvironment in Colorectal Cancer Patients.

Manuel Collado, Marién Castillo, Gemma Julia Muñoz de Mier, Carolina de la Pinta, Cristina Peña.

  Colorectal cancer (CRC) is one of the most common cancers in Western countries and remains the second most common cause of cancer death worldwide. Many studies show the importance of diet and lifestyle in the incidence of CRC, as well as in CRC prevention. However, this review summarizes those studies that analyze the impact of nutrition on tumor microenvironment modulation and cancer progression. We review the available information about the effects of specific nutrients on cancer cell progression and on the different cells within the tumor microenvironment. Diet and nutritional status in the clinical management of colorectal cancer patients are also analyzed. Finally, future perspectives and challenges are discussed, with a view to improving CRC treatments by employing nutritional approaches. These promise great benefits and will eventually improve CRC patients' survival.

Keywords:  colorectal cancer; diet; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms24087317
Stem Cells. 2023 Apr 25. 41(4): 307-309

Advances in Stem Cell Immunotherapy.

Johnathon D Anderson.

DOI: https://doi.org/10.1093/stmcls/sxad011
Adv Mater. 2023 Apr 26. e2209785

Recruiting T Cells towards Brain for Enhanced Glioblastoma Immunotherapeutic Efficacy by Co-delivery of Cytokines and Immune Checkpoint Antibodies with Macrophage Membrane-Camouflaged Nano Vesicles.

Xiaoxuan Xu, Zhiqi Zhang, Jiawei Du, Yonger Xue, Xin Chen, Jianqiong Zhang, Xue Yang, Di Chang, Jinbing Xie, Shenghong Ju.

  Immunotherapy with immune checkpoint inhibitors (CPIs) shows promising prospects for glioblastoma multiforme (GBM) while with restricted results, mainly attributed to the immunosuppressive tumor microenvironment (TME) and the limited antibody permeability of blood-tumor-barrier (BTB) in GBM. Here, we described a macrophage-mimicking membrane vesicle that co-delivering chemotactic CXC chemokine ligand 10 (CXCL10) to pre-activate the immune microenvironment and anti-programmed death ligand 1 antibody (aPD-L1) to interrupt the immune checkpoint, aiming to enhance the effect of GBM immunotherapy. Consequently, tumor tropism of macrophage membrane and receptor mediated transcytosis of angiopeptide-2 peptide allowed the nano vesicle to effectively cross the BTB and target GBM region, with 19.75-fold higher antibodies accumulation compared to free aPD-L1 group. The CPI therapeutic efficacy was greatly enhanced by CXCL10 induced T cells recruitment with significant expansion of CD8+ T cells and effector memory T cells, leading to the elimination of tumor, prolonged survival time and long-term immune memory in the orthotopic GBM mice. The nano vesicle that relieving tumor immunosuppressive microenvironment by CXCL10 to enhance aPD-L1 efficacy might present a promising strategy for brain-tumor immunotherapy. This article is protected by copyright. All rights reserved.

Keywords:  CXCL10; blood-tumor-barrier; glioblastoma multiforme; immune checkpoint inhibitors; immunosuppressive microenvironment; nano vesicle

DOI:  https://doi.org/10.1002/adma.202209785
Biochem Biophys Res Commun. 2023 Apr 19. pii: S0006-291X(23)00474-6. [Epub ahead of print]662 1-7

The characterization of the sensitive ovarian cancer cell lines A2780 and W1 in response to ovarian CAFs.

Karolina Wojtowicz, Michał Nowicki.

   PURPOSE: The cancer-associated fibroblasts (CAFs) are one of the most abundant components of the tumor microenvironment (TME). CAFs have been implicated in tumor progression, extracellular matrix (ECM) remodeling, and treatment resistance. Drug resistance is the primary limiting factor in achieving cures for patients with cancer, particularly ovarian cancer. Therefore, inhibiting CAFs can be an effective strategies for cancer treatment. In this research, we studied whether CAFs have an influence on drug-sensitive ovarian cancer cells to become more resistant. We examined the influence of CAFs on genes and proteins expression changes in sensitive ovarian cancer cells. We prepared a 3D co-culture to investigate the role of CAFs on cancer cell morphology.
METHODS: Here, we performed a detailed analysis of drug-sensitive ovarian cancer cell lines (A2780 and W1) and the influence of ovarian CAFs on the A2780 and W1 cells morphology, genes and proteins expression. The 2D and 3D cultures, genes expression analysis (TaqMan qPCR), and proteins expression (Western blot analysis) were assessed in this study.
RESULTS: We observed upregulation of ABCC5, CYP2C8, CYP2C9, and DHFR mRNA in cell lines supplemented by CAFs medium. We showed fibronectin overexpression and COL3A1 downregulation after supplementation with CAFs. Co-culturing with CAFs prevented the formation of spheroids in 3D conditions.
CONCLUSION: We demonstrated that the process of drug resistance in ovarian cancer cells is launched by CAFs. CAFs not only simulate cancer cells to produce drug transporters and specific enzymes production, but also remodel the TME to increase drug resistance. We believe that cancer progression and migration is due to the CAFs po-tumorigenic activity.

Keywords:  CAFs; Cancer associated fibroblast; Drug resistance; Ovarian cancer cell lines

DOI:  https://doi.org/10.1016/j.bbrc.2023.04.059
Signal Transduct Target Ther. 2023 Apr 28. 8(1): 164

Overcoming resistance to immunotherapy by targeting GPR84 in myeloid-derived suppressor cells.

Guohui Qin, Shasha Liu, Jinyan Liu, Hongwei Hu, Li Yang, Qitai Zhao, Congcong Li, Bin Zhang, Yi Zhang.

Myeloid-derived suppressor cells (MDSCs) were found to gradually accumulate in the orthotopic esophageal cancer mouse model during tumor progression. Although the roles of MDSCs in promoting tumor growth and inhibiting immune response have been extensively explored, currently, there are still no effective means for targeting MDSCs clinically. The deficiency of specific markers of MDSCs was responsible for the limited strategy to eliminating in clinic. This study identified that GPR84 was exclusively overexpressed on MDSCs. It was further found that GPR84 was prominently expressed on MDSCs in clinical samples and tumor mouse models, which drives the immunosuppression on CD8+T cells by inhibiting PD-L1 degradation in lysosomes. Furthermore, G-CSF and GM-CSF were found to induce GPR84 expression through the STAT3/C/EBPβ signaling pathway. In addition, GPR84+MDSCs and PD-L1+MDSCs were highly accumulated in anti-PD-1 therapy-resistant patients with esophageal cancer, and high GPR84 signature risk was verified as a negative factor for the overall survival of patients with anti-PD-1 treatment. Finally, GPR84 antagonism combined with an anti-PD-1 antibody enhanced the antitumor responses. Therefore, targeting GPR84 enhanced anti-PD-1 efficacy in esophageal cancer and other malignant tumors. This combination therapy has the potential for tumor therapy in clinics.

DOI: https://doi.org/10.1038/s41392-023-01388-6
Int J Mol Sci. 2023 Apr 18. pii: 7463. [Epub ahead of print]24(8):

Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses.

Beatrice Foglia, Marc Beltrà, Salvatore Sutti, Stefania Cannito.

  Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading causes of cancer-related mortality worldwide and whose incidence varies according to geographical area and ethnicity. Metabolic rewiring was recently introduced as an emerging hallmark able to affect tumor progression by modulating cancer cell behavior and immune responses. This review focuses on the recent studies examining HCC's metabolic traits, with particular reference to the alterations of glucose, fatty acid and amino acid metabolism, the three major metabolic changes that have gained attention in the field of HCC. After delivering a panoramic picture of the peculiar immune landscape of HCC, this review will also discuss how the metabolic reprogramming of liver cancer cells can affect, directly or indirectly, the microenvironment and the function of the different immune cell populations, eventually favoring the tumor escape from immunosurveillance.

Keywords:  HCC; TCA cycle; amino acid metabolism; fatty acid metabolism; glucose metabolism; glutamine; immune response; metabolic reprogramming; tumor microenvironment; urea cycle

DOI:  https://doi.org/10.3390/ijms24087463
J Transl Med. 2023 Apr 22. 21(1): 275

The "Great Debate" at Immunotherapy Bridge 2022, Naples, November 30th-December 1st, 2022.

Paolo A Ascierto, Renier Brentjens, Samir N Khleif, Kunle Odunsi, Katayoun Rezvani, Marco Ruella, Ryan J Sullivan, Bernard A Fox, Igor Puzanov.

  The 2022 Immunotherapy Bridge congress (November 30-December 1, Naples, Italy) featured a Great Debate session which addressed three contemporary topics in the field of immunotherapy. The debates included counterpoint views from leading experts and considered whether adoptive cell therapy (ACT) has a role in the treatment of solid tumors, the use of peripheral/blood biomarkers versus tumor microenvironment biomarkers for cancer immunotherapy and the role of chimeric antigen receptor T cell versus natural killer cell therapy. As is the tradition in the Immunotherapy Bridge Great Debates, speakers are invited by the meeting Chairs to express one side of the assigned debate and the opinions given may not fully reflect their own personal views. Audiences voted in favour of either side of the topic both before and after each debate.

Keywords:  Adoptive cell therapy; Biomarkers; CAR therapy; Cancer; Immunotherapy

DOI:  https://doi.org/10.1186/s12967-023-04117-3
Proc Natl Acad Sci U S A. 2023 May 02. 120(18): e2218033120

Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF-nuclear IL-33-GATA3 pathway.

Miho Akimoto, Takao Susa, Noriyuki Okudaira, Nobuko Koshikawa, Harumi Hisaki, Masayoshi Iizuka, Hiroko Okinaga, Keizo Takenaga, Tomoki Okazaki, Mimi Tamamori-Adachi.

  As a decoy receptor, soluble ST2 (sST2) interferes with the function of the inflammatory cytokine interleukin (IL)-33. Decreased sST2 expression in colorectal cancer (CRC) cells promotes tumor growth via IL-33-mediated bioprocesses in the tumor microenvironment. In this study, we discovered that hypoxia reduced sST2 expression in CRC cells and explored the associated molecular mechanisms, including the expression of key regulators of ST2 gene transcription in hypoxic CRC cells. In addition, the effect of the recovery of sST2 expression in hypoxic tumor regions on malignant progression was investigated using mouse CRC cells engineered to express sST2 in response to hypoxia. Our results indicated that hypoxia-dependent increases in nuclear IL-33 interfered with the transactivation activity of GATA3 for ST2 gene transcription. Most importantly, hypoxia-responsive sST2 restoration in hypoxic tumor regions corrected the inflammatory microenvironment and suppressed tumor growth and lung metastasis. These results indicate that strategies targeting sST2 in hypoxic tumor regions could be effective for treating malignant CRC.

Keywords:  colorectal cancer; hypoxia; interleukin-33; metastasis; soluble ST2

DOI:  https://doi.org/10.1073/pnas.2218033120
Biochim Biophys Acta Rev Cancer. 2023 Apr 17. pii: S0304-419X(23)00045-8. [Epub ahead of print]1878(3): 188896

Regulation of cGAS-STING signalling in cancer: Approach for combination therapy.

Hitesh Vasiyani, Bhumika Wadhwa, Rajesh Singh.

  Innate immunity plays an important role not only during infection but also homeostatic role during stress conditions. Activation of the immune system including innate immune response plays a critical role in the initiation and progression of tumorigenesis. The innate immune sensor recognizes pathogen-associated molecular patterns (PAMPs) and activates cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) (cGAS-STING) and induces type-1 immune response during viral and bacterial infection. cGAS-STING is regulated differently in conditions like cellular senescence and DNA damage in normal and tumor cells and is implicated in the progression of tumors from different origins. cGAS binds to cytoplasmic dsDNA and synthesize cyclic GMP-AMP (2'3'-cGAMP), which selectively activates STING and downstream IFN and NF-κB activation. We here reviewed the cGAS-STING signalling pathway and its cross-talk with other pathways to modulate tumorigenesis. Further, the review also focused on emerging studies that targeted the cGAS-STING pathway for developing targeted therapeutics and combinatorial regimens for cancer of different origins.

Keywords:  Cancer; Chromosomal instability; Classical therapy; Combinatorial therapy; Immunomodulatory; Tumor microenvironment; cGAS-STING

DOI:  https://doi.org/10.1016/j.bbcan.2023.188896
Trends Cell Biol. 2023 Apr 24. pii: S0962-8924(23)00077-6. [Epub ahead of print]

A metabolic clue for STING suppression.

Yifan Zhang, Ming-Zhu Lei, Miao Yin, Qun-Ying Lei.

  A recent report by Heath et al. reveals that obesity could impair cancer immunogenicity and foster a type I interferon (IFN-I)-deprived tumor microenvironment through saturated fatty acid-mediated stimulator of interferon genes (STING) inhibition.

Keywords:  STING; antitumor immunity; fatty acids; obesity

DOI:  https://doi.org/10.1016/j.tcb.2023.04.003
Breast Cancer Res. 2023 Apr 25. 25(1): 46

Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer.

Soojung Lee, Nicolai J Toft, Trine V Axelsen, Maria Sofia Espejo, Tina M Pedersen, Marco Mele, Helene L Pedersen, Eva Balling, Tonje Johansen, Mark Burton, Mads Thomassen, Pernille Vahl, Peer Christiansen, Ebbe Boedtkjer.

   BACKGROUND: Carbonic anhydrases catalyze CO2/HCO3- buffer reactions with implications for effective H+ mobility, pH dynamics, and cellular acid-base sensing. Yet, the integrated consequences of carbonic anhydrases for cancer and stromal cell functions, their interactions, and patient prognosis are not yet clear.
METHODS: We combine (a) bioinformatic analyses of human proteomic data and bulk and single-cell transcriptomic data coupled to clinicopathologic and prognostic information; (b) ex vivo experimental studies of gene expression in breast tissue based on quantitative reverse transcription and polymerase chain reactions, intracellular and extracellular pH recordings based on fluorescence confocal microscopy, and immunohistochemical protein identification in human and murine breast cancer biopsies; and (c) in vivo tumor size measurements, pH-sensitive microelectrode recordings, and microdialysis-based metabolite analyses in mice with experimentally induced breast carcinomas.
RESULTS: Carbonic anhydrases-particularly the extracellular isoforms CA4, CA6, CA9, CA12, and CA14-undergo potent expression changes during human and murine breast carcinogenesis. In patients with basal-like/triple-negative breast cancer, elevated expression of the extracellular carbonic anhydrases negatively predicts survival, whereas, surprisingly, the extracellular carbonic anhydrases positively predict patient survival in HER2/ErbB2-enriched breast cancer. Carbonic anhydrase inhibition attenuates cellular net acid extrusion and extracellular H+ elimination from diffusion-restricted to peripheral and well-perfused regions of human and murine breast cancer tissue. Supplied in vivo, the carbonic anhydrase inhibitor acetazolamide acidifies the microenvironment of ErbB2-induced murine breast carcinomas, limits tumor immune infiltration (CD3+ T cells, CD19+ B cells, F4/80+ macrophages), lowers inflammatory cytokine (Il1a, Il1b, Il6) and transcription factor (Nfkb1) expression, and accelerates tumor growth. Supporting the immunomodulatory influences of carbonic anhydrases, patient survival benefits associated with high extracellular carbonic anhydrase expression in HER2-enriched breast carcinomas depend on the tumor inflammatory profile. Acetazolamide lowers lactate levels in breast tissue and blood without influencing breast tumor perfusion, suggesting that carbonic anhydrase inhibition lowers fermentative glycolysis.
CONCLUSIONS: We conclude that carbonic anhydrases (a) elevate pH in breast carcinomas by accelerating net H+ elimination from cancer cells and across the interstitial space and (b) raise immune infiltration and inflammation in ErbB2/HER2-driven breast carcinomas, restricting tumor growth and improving patient survival.

Keywords:  Acetazolamide; Acidosis; Breast cancer; Carbonic anhydrases; ErbB2; HER2; Immuno-oncology; Metabolism; Perfusion; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13058-023-01644-1
Bio Protoc. 2023 Apr 20. 13(8): e4655

Anti-tumor Efficacy of CD19 CAR-T in a Raji B Cell Xenografted Mouse Model.

Qian Xiao, Xiaolei Su.

  Chimeric antigen receptor (CAR)-T therapy launched a new era for cancer treatments, displaying outstanding effectiveness in relapsed or refractory B-cell malignancies. Demonstrating the tumor-killing ability of CAR-Ts in mouse xenograft models serves as a golden criterium in preclinical research. Here, we describe a detailed method for evaluating CAR-T's function in immune-deficient mice bearing Raji B cell-induced tumors. It includes generating CD19 CAR-T cells from healthy donors, injecting tumor cells and CAR-T cells into mice, and monitoring tumor growth and CAR-T state. This protocol provides a practical guide to evaluate CAR-T's function in vivo within eight weeks. Graphical abstract.

Keywords:  CD19 CAR-T; Chimeric antigen receptor; In vivo tumor killing assay; Raji B cell; Xenografted tumor model

DOI:  https://doi.org/10.21769/BioProtoc.4655