bims-flamet 2024-07-21 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–07–21
29 papers selected by
Peio Azcoaga, Biodonostia HRI

An update to experimental and clinical aspects of tumor-associated macrophages in cancer development: hopes and pitfalls.
Metabolic heterogeneity in tumor microenvironment - A novel landmark for immunotherapy.
Pancreatic ductal adenocarcinoma microenvironment: soluble factors and cancer associated fibroblasts as modulators of NK cell functions.
Impact and potential value of immunosenescence on solid gastrointestinal tumors.
CAR-T cell technologies that interact with the tumour microenvironment in solid tumours.
Cancer-associated fibroblasts mediate resistance to anti-EGFR therapies in cancer.
Ferroptosis crosstalk in anti-tumor immunotherapy: molecular mechanisms, tumor microenvironment, application prospects.
Autophagy as a Therapeutic Target in Breast Tumors: The Cancer stem cell perspective.
Application of CAR-T cell therapy targeting mesothelin in solid tumor treatment.
PARP11 inhibition inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies.
Amelioration of breast cancer therapies through normalization of tumor vessels and microenvironment: paradigm shift to improve drug perfusion and nanocarrier permeation.
The role of signaling lymphocyte activation molecule family receptors in hematologic malignancies.
Estrogen receptor blockade potentiates immunotherapy for liver metastases by altering the liver immunosuppressive microenvironment.
Interplay between oncolytic measles virus, macrophages and cancer cells induces a proinflammatory tumor microenvironment.
Plasmacytoid dendritic cells at the forefront of anti-cancer immunity: rewiring strategies for tumor microenvironment remodeling.
Acidity and hypoxia of tumor microenvironment, a positive interplay in extracellular vesicle release by tumor cells.
The role of bone marrow microenvironment on CAR-T efficacy in haematologic malignancies.
The role of CD8+ T-cells in colorectal cancer immunotherapy.
Non-genetic heterogeneity and immune subtyping in breast cancer: Implications for immunotherapy and targeted therapeutics.
Targeting endothelial cell anergy to improve CAR T cell therapy for solid tumors.
Glucocorticoids in lung cancer: Navigating the balance between immunosuppression and therapeutic efficacy.
Advancements in nanomedicine delivery systems: unraveling immune regulation strategies for tumor immunotherapy.
[Immunomodulation in the tumor microenvironment: Therapeutic potential of combined inhibition of tumor hypoxia and PD-1/ PD-L1].
Reprogramming Tumor-Associated Macrophages with a Se-Based Core-Satellite Nanoassembly to Enhance Cancer Immunotherapy.
Panoramic tumor microenvironment in pancreatic ductal adenocarcinoma.
The role of tissue-derived extracellular vesicles in tumor microenvironment.
The potential role of CD8+ cytotoxic T lymphocytes and one branch connected with tissue-resident memory in non-luminal breast cancer.
FABP4-mediated lipid accumulation and lipolysis in tumor associated macrophages promote breast cancer metastasis.
Reactive oxygen species of tumor microenvironment: Harnessing for immunogenic cell death.

Clin Exp Med. 2024 Jul 13. 24(1): 156

An update to experimental and clinical aspects of tumor-associated macrophages in cancer development: hopes and pitfalls.

Arash Salmaninejad, Sepideh Mehrpour Layeghi, Zeinab Falakian, Shahin Golestani, Sepehr Kobravi, Samaneh Talebi, Meysam Yousefi.

  Tumor-associated macrophages (TAMs) represent one of the most abundant tumor-infiltrating stromal cells, and their normal function in tumor microenvironment (TME) is to suppress tumor cells by producing cytokines which trigger both direct cell cytotoxicity and antibody-mediated immune response. However, upon prolonged exposure to TME, the classical function of these so-called M1-type TAMs can be converted to another type, "M2-type," which are recruited by tumor cells so that they promote tumor growth and metastasis. This is the reason why the accumulation of TAMs in TME is correlated with poor prognosis in cancer patients. Both M1- and M2-types have high degree of plasticity, and M2-type cells can be reprogrammed to M1-type for therapeutic purposes. This characteristic introduces TAMs as promising target for developing novel cancer treatments. In addition, inhibition of M2-type cells and blocking their recruitment in TME, as well as their depletion by inducing apoptosis, are other approaches for effective immunotherapy of cancer. In this review, we summarize the potential of TAMs to be targeted for cancer immunotherapy and provide an up-to-date about novel strategies for targeting TAMs.

Keywords:  Cancer development; Metastasis; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1007/s10238-024-01417-w
Autoimmun Rev. 2024 Jul 12. pii: S1568-9972(24)00070-3. [Epub ahead of print] 103579

Metabolic heterogeneity in tumor microenvironment - A novel landmark for immunotherapy.

Chen Chen, Peng Han, Yanping Qing.

  The surrounding non-cancer cells and tumor cells that make up the tumor microenvironment (TME) have various metabolic rhythms. TME metabolic heterogeneity is influenced by the intricate network of metabolic control within and between cells. DNA, protein, transport, and microbial levels are important regulators of TME metabolic homeostasis. The effectiveness of immunotherapy is also closely correlated with alterations in TME metabolism. The response of a tumor patient to immunotherapy is influenced by a variety of variables, including intracellular metabolic reprogramming, metabolic interaction between cells, ecological changes within and between tumors, and general dietary preferences. Although immunotherapy and targeted therapy have made great strides, their use in the accurate identification and treatment of tumors still has several limitations. The function of TME metabolic heterogeneity in tumor immunotherapy is summarized in this article. It focuses on how metabolic heterogeneity develops and is regulated as a tumor progresses, the precise molecular mechanisms and potential clinical significance of imbalances in intracellular metabolic homeostasis and intercellular metabolic coupling and interaction, as well as the benefits and drawbacks of targeted metabolism used in conjunction with immunotherapy. This offers insightful knowledge and important implications for individualized tumor patient diagnosis and treatment plans in the future.

Keywords:  Immunotherapy; Metabolic crosstalk; Metabolic heterogeneity; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.autrev.2024.103579
Immunol Lett. 2024 Jul 15. pii: S0165-2478(24)00072-5. [Epub ahead of print] 106898

Pancreatic ductal adenocarcinoma microenvironment: soluble factors and cancer associated fibroblasts as modulators of NK cell functions.

Simona Carlomagno, Chiara Setti, Fulvia Ortolani, Simona Sivori.

  Pancreatic Ductal Adenocarcinoma (PDAC) is the most frequent pancreatic cancer and represents one of the most aggressive human neoplasms. Typically identified at advance stage disease, most PDAC tumors are unresectable and resistant to standard therapies. The immunosuppressive microenvironment in PDAC impedes tumor control but a greater understanding of the complex stromal interactions within the tumor microenvironment (TME) and the development of strategies capable of restoring antitumor effector immune responses could be crucial to fight this aggressive tumor and its spread. Natural killer (NK) cells play a crucial role in cancer immunosurveillance and represent an attractive target for immunotherapies, both as cell therapy and as a pharmaceutical target. This review describes some crucial components of the PDAC TME (collagens, soluble factors and fibroblasts) that can influence the presence, phenotype and function of NK cells in PDAC patients tumor tissue. This focused overview highlights the therapeutic relevance of dissecting the complex stromal composition to define new strategies for NK cell-based immunotherapies to improve the treatment of PDAC.

Keywords:  Cancer Associated Fibroblasts; Natural Killer cells; Pancreatic cancer; collagen; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.imlet.2024.106898
Front Immunol. 2024 ;15 1375730

Impact and potential value of immunosenescence on solid gastrointestinal tumors.

Tianshuai Zhang, Rongbo Wen, Hao Fan, Yue Yu, Hang Jia, Zhiying Peng, Leqi Zhou, Guanyu Yu, Wei Zhang.

  Solid gastrointestinal tumors often respond poorly to immunotherapy for the complex tumor microenvironment (TME), which is exacerbated by immune system alterations. Immunosenescence is the process of increased diversification of immune genes due to aging and other factors, leading to a decrease in the recognition function of the immune system. This process involves immune organs, immune cells, and the senescence-associated secretory phenotype (SASP). The most fundamental change is DNA damage, resulting in TME remodeling. The main manifestations are worsening inflammation, increased immunosuppressive SASP production, decreased immune cell antitumor activity, and the accumulation of tumor-associated fibroblasts and myeloid-derived suppressor cells, making antitumor therapy less effective. Senotherapy strategies to remove senescent cells and block key senescence processes can have synergistic effects with other treatments. This review focuses on immunoenescence and its impact on the solid TME. We characterize the immunosenescent TME and discuss future directions for antitumor therapies targeting senescence.

Keywords:  colorectal cancer; gastrointestinal tumors; immunosenescence; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1375730
Expert Rev Clin Immunol. 2024 Jul 17. 1-23

CAR-T cell technologies that interact with the tumour microenvironment in solid tumours.

Chelsea Alice Taylor, Maya Glover, John Maher.

   INTRODUCTION: Chimeric antigen receptor (CAR) T-cells have emerged as a ground-breaking therapy for the treatment of hematological malignancies due to their capacity for rapid tumor-specific killing and long-lasting tumor immunity. However, the same success has not been observed in patients with solid tumors. Largely, this is due to the additional challenges imposed by safe and uniform target selection, inefficient CAR T-cell access to sites of disease and the presence of a hostile immunosuppressive tumor microenvironment.
AREAS COVERED: Literature was reviewed on the PubMed database from the first description of a CAR by Kuwana, Kurosawa and colleagues in December 1987 through to the present day. This literature indicates that in order to tackle solid tumors, CAR T-cells can be further engineered with additional armoring strategies that facilitate trafficking to and infiltration of malignant lesions together with reversal of suppressive immune checkpoints that operate within solid tumor lesions.
EXPERT OPINION: In this review, we describe a number of recent advances in CAR T-cell technology that set out to combat the problems imposed by solid tumors including tumor recruitment, infiltration, immunosuppression, metabolic compromise, and hypoxia.

Keywords:  Chimeric antigen receptor (CAR); cancer-associated fibroblasts (CAFs); chemokine receptors; extracellular matrix (ECM); hypoxia; immune checkpoint proteins; tumor microenvironment (TME); tumor vasculature

DOI:  https://doi.org/10.1080/1744666X.2024.2380894
Pharmacol Res. 2024 Jul 11. pii: S1043-6618(24)00249-4. [Epub ahead of print] 107304

Cancer-associated fibroblasts mediate resistance to anti-EGFR therapies in cancer.

Shuang Dai, Yingtong Liu, Zheran Liu, Ruidan Li, Feng Luo, Yan Li, Lei Dai, Xingchen Peng.

  Over the last decade, epidermal growth factor receptor (EGFR)-targeted therapies have transformed the treatment landscape for patients with advanced solid tumors. Despite these advances, resistance to anti-EGFR therapies is still a significant clinical challenge. While cell-autonomous mechanisms of resistance are well-documented, they do not fully elucidate the complexity of drug resistance. Cancer-associated fibroblasts (CAFs), key mediators within the tumor microenvironment (TME), have emerged as pivotal players in cancer progression and chemoresistance. Recent evidence implicates CAFs in resistance to anti-EGFR therapies, suggesting they may undermine treatment efficacy. This review synthesizes current data, highlighting the critical role of CAFs in resistance pathogenesis and summarizing recent therapeutic strategies targeting CAFs. We underscore the challenges and advocate for the exploration of CAFs as a potential dual-targeted approach.

Keywords:  Epidermal growth factor receptor; anti-EGFR therapy; cancer-associated fibroblast; resistance; tumor microenvironment

DOI:  https://doi.org/10.1016/j.phrs.2024.107304
Apoptosis. 2024 Jul 15.

Ferroptosis crosstalk in anti-tumor immunotherapy: molecular mechanisms, tumor microenvironment, application prospects.

Yining Lu, Xiaoting Xie, Lianxiang Luo.

  Immunotherapies for cancer, specifically immune checkpoint inhibition (ICI), have shown potential in reactivating the body's immune response against tumors. However, there are challenges to overcome in addressing drug resistance and improving the effectiveness of these treatments. Recent research has highlighted the relationship between ferroptosis and the immune system within immune cells and the tumor microenvironment (TME), suggesting that combining targeted ferroptosis with immunotherapy could enhance anti-tumor effects. This review explores the potential of using immunotherapy to target ferroptosis either alone or in conjunction with other therapies like immune checkpoint blockade (ICB) therapy, radiotherapy, and nanomedicine synergistic treatments. It also delves into the roles of different immune cell types in promoting anti-tumor immune responses through ferroptosis. Together, these findings provide a comprehensive understanding of synergistic immunotherapy focused on ferroptosis and offer innovative strategies for cancer treatment.

Keywords:  Ferroptosis; Immune cells; Immunotherapy; Lipid peroxidation; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10495-024-01997-8
Autophagy Rep. 2024 Dec 31. pii: 27694127.2024.2358648. [Epub ahead of print]3(1):

Autophagy as a Therapeutic Target in Breast Tumors: The Cancer stem cell perspective.

Sana Raza, Jawed Akhtar Siddiqui, Anubhav Srivastava, Naibedya Chattopadhyay, Rohit Anthony Sinha, Bandana Chakravarti.

  Breast cancer is a heterogeneous disease, with a subpopulation of tumor cells known as breast cancer stem cells (BCSCs) with self-renewal and differentiation abilities that play a critical role in tumor initiation, progression, and therapy resistance. The tumor microenvironment (TME) is a complex area where diverse cancer cells reside creating a highly interactive environment with secreted factors, and the extracellular matrix. Autophagy, a cellular self-digestion process, influences dynamic cellular processes in the tumor TME integrating diverse signals that regulate tumor development and heterogeneity. Autophagy acts as a double-edged sword in the breast TME, with both tumor-promoting and tumor-suppressing roles. Autophagy promotes breast tumorigenesis by regulating tumor cell survival, migration and invasion, metabolic reprogramming, and epithelial-mesenchymal transition (EMT). BCSCs harness autophagy to maintain stemness properties, evade immune surveillance, and resist therapeutic interventions. Conversely, excessive, or dysregulated autophagy may lead to BCSC differentiation or cell death, offering a potential avenue for therapeutic exploration. The molecular mechanisms that regulate autophagy in BCSCs including the mammalian target of rapamycin (mTOR), AMPK, and Beclin-1 signaling pathways may be potential targets for pharmacological intervention in breast cancer. This review provides a comprehensive overview of the relationship between autophagy and BCSCs, highlighting recent advancements in our understanding of their interplay. We also discuss the current state of autophagy-targeting agents and their preclinical and clinical development in BCSCs.

Keywords:  Autophagy; Breast Cancer; Breast Cancer stem cells; Metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1080/27694127.2024.2358648
Discov Oncol. 2024 Jul 18. 15(1): 289

Application of CAR-T cell therapy targeting mesothelin in solid tumor treatment.

Qiuhong Chen, Yang Sun, Hua Li.

  Chimeric antigen receptor (CAR)-T-cell therapy is one of the most effective immunotherapies. CAR-T-cell therapy has achieved great success in the treatment of hematological malignancies. However, due to the characteristics of solid malignant tumors, such as on-target effects, off-tumor toxicity, an immunosuppressive tumor microenvironment (TME), and insufficient trafficking, CAR-T-cell therapy for solid tumors is still in the exploration stage. Mesothelin (MSLN) is a molecule expressed on the surface of various solid malignant tumor cells that is suitable as a target of tumor cells with high MSLN expression for CAR-T-cell therapy. This paper briefly described the development of CAR-T cell therapy and the structural features of MSLN, and especially summarized the strategies of structure optimization of MSLN-targeting CAR-T-cells and the enhancement methods of MSLN-targeting CAR-T cell anti-tumor efficacy by summarizing some preclinical experiment and clinical trials. When considering MSLN-targeting CAR-T-cell therapy as an example, this paper summarizes the efforts made by researchers in CAR-T-cell therapy for solid tumors and summarizes feasible treatment plans by integrating the existing research results.

Keywords:  CAR-T cell therapy; Mesothelin; Solid tumors

DOI:  https://doi.org/10.1007/s12672-024-01159-x
Cell Rep Med. 2024 Jul 16. pii: S2666-3791(24)00363-X. [Epub ahead of print]5(7): 101649

PARP11 inhibition inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies.

Raghavendra Basavaraja, Hongru Zhang, Ágnes Holczbauer, Zhen Lu, Enrico Radaelli, Charles-Antoine Assenmacher, Subin S George, Vamshidhar C Nallamala, Daniel P Beiting, Mirella L Meyer-Ficca, Ralph G Meyer, Wei Guo, Yi Fan, Andrew J Modzelewski, Vladimir S Spiegelman, Michael S Cohen, Serge Y Fuchs.

  Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenvironment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here, we demonstrate that poly-(ADP-ribose)-polymerase-11 (PARP11) is an essential regulator of immunosuppressive activities of TI-Tregs. Expression of PARP11 correlates with TI-Treg cell numbers and poor responses to immune checkpoint blockade (ICB) in human patients with cancer. Tumor-derived factors including adenosine and prostaglandin E2 induce PARP11 in TI-Tregs. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivates TI-Tregs and reinvigorates anti-tumor immune responses. Accordingly, ITK7 decelerates tumor growth and significantly increases the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of chimeric antigen receptor (CAR) T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies.

Keywords:  ITK7; PARP11; PARP11 inhibitor; Treg cells; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2024.101649
Drug Deliv Transl Res. 2024 Jul 15.

Amelioration of breast cancer therapies through normalization of tumor vessels and microenvironment: paradigm shift to improve drug perfusion and nanocarrier permeation.

Paras Famta, Saurabh Shah, Ganesh Vambhurkar, Giriraj Pandey, Deepkumar Bagasariya, Kondasingh Charan Kumar, Sajja Bhanu Prasad, Akshay Shinde, Suraj Wagh, Dadi A Srinivasarao, Rahul Kumar, Dharmendra Kumar Khatri, Amit Asthana, Saurabh Srivastava.

  Breast cancer (BC) is the most commonly diagnosed cancer among women. Chemo-, immune- and photothermal therapies are employed to manage BC. However, the tumor microenvironment (TME) prevents free drugs and nanocarriers (NCs) from entering the tumor premises. Formulation scientists rely on enhanced permeation and retention (EPR) to extravasate NCs in the TME. However, recent research has demonstrated the inconsistent nature of EPR among different patients and tumor types. In addition, angiogenesis, high intra-tumor fluid pressure, desmoplasia, and high cell and extracellular matrix density resist the accumulation of NCs in the TME. In this review, we discuss TME normalization as an approach to improve the penetration of drugs and NCSs in the tumor premises. Strategies such as normalization of tumor vessels, reversal of hypoxia, alleviation of high intra-tumor pressure, and infiltration of lymphocytes for the reversal of therapy failure have been discussed in this manuscript. Strategies to promote the infiltration of anticancer immune cells in the TME after vascular normalization have been discussed. Studies strategizing time points to administer TME-normalizing agents are highlighted. Mechanistic pathways controlling the angiogenesis and normalization processes are discussed along with the studies. This review will provide greater tumor-targeting insights to the formulation scientists.

Keywords:  Angiogenesis; Chemotherapy; Immunotherapy; Mechanotherapeutics; Tumor microenvironment normalization

DOI:  https://doi.org/10.1007/s13346-024-01669-9
Curr Opin Oncol. 2024 Jun 20.

The role of signaling lymphocyte activation molecule family receptors in hematologic malignancies.

Louis Boafo Kwantwi, Steven T Rosen, Christiane Querfeld.

PURPOSE OF REVIEW: In this review, we provide an overview of the current understanding of SLAM-family receptors in hematologic malignancies. We highlighted their contribution to the disease pathogenesis and targeting strategies to improve therapeutic outcomes.
RECENT FINDINGS: Emerging studies have reported the tumor-promoting role of SLAM-family receptors in various hematologic malignancies, including chronic lymphocytic leukemia, acute myeloid leukemia, and multiple myeloma. Specifically, they regulate the interaction between malignant cells and the tumor microenvironment to promote apoptosis resistance, therapeutic resistance, impairment of antitumor and tumor progression.
SUMMARY: SLAM-family receptors promote the progression of hematologic malignancies by regulating the interaction between malignant cells and the tumor microenvironment. This provides the rationale that SLAM-targeted therapies are appealing strategies to enhance therapeutic outcomes in patients.

DOI: https://doi.org/10.1097/CCO.0000000000001067
Cancer Res Commun. 2024 Jul 15.

Estrogen receptor blockade potentiates immunotherapy for liver metastases by altering the liver immunosuppressive microenvironment.

Yasmine Benslimane, Kevin Amalfi, Sarah Lapin, Stephanie Perrino, Pnina Brodt.

Liver metastases (LM) remain a major cause of cancer-related death and are a major clinical challenge. Liver metastases and the female sex are predictors of a poorer response to immunotherapy, but the underlying mechanisms remain unclear. We previously reported on a sexual dimorphism in the control of the tumor microenvironment (TME) of CRC liver metastases (CRCLM) and identified estrogen as a regulator of an immunosuppressive TME in the liver. Here we aimed to assess the effect of estrogen deprivation on the cytokine/chemokine profile associated with CRCLM, using a Multiplex Cytokine Array and the RNAscope technology, and its effects on the innate and adaptive immune responses in the liver. We also evaluated the benefit of combining the selective estrogen-receptor degrader Fulvestrant with immune checkpoint blockade for treatment of CRCLM. We show that estrogen depletion altered the cytokine/chemokine repertoire of the liver, decreased macrophage polarization as reflected in reduced accumulation of tumor infiltrating M2 macrophages and increased the accumulation of CCL5+/CCR5+ CD8+ T and NKT cells in the liver TME. Similar results were obtained in a murine pancreatic ductal adenocarcinoma model. Importantly, treatment with Fulvestrant also increased the accumulation of CD8+CCL5+, CD8+CCR5+ T and NK cells in the liver TME and enhanced the therapeutic benefit of anti-PD1 immunotherapy, resulting in a significant reduction in the outgrowth of LM. Taken together, our results show that estrogen regulates immune cells recruitment to the liver and suggest that inhibition of estrogen action could potentiate the tumor-inhibitory effect of immunotherapy in hormone-independent and IT-resistant metastatic cancer.

DOI: https://doi.org/10.1158/2767-9764.CRC-24-0196
Oncoimmunology. 2024 ;13(1): 2377830

Interplay between oncolytic measles virus, macrophages and cancer cells induces a proinflammatory tumor microenvironment.

Camille Chatelain, Laurine Berland, Marion Grard, Nicolas Jouand, Judith Fresquet, Joëlle Nader, Ugo Hirigoyen, Tacien Petithomme, Chantal Combredet, Elvire Pons-Tostivint, Delphine Fradin, Lucas Treps, Christophe Blanquart, Nicolas Boisgerault, Frédéric Tangy, Jean-François Fonteneau.

  Attenuated measles virus (MV) exerts its oncolytic activity in malignant pleural mesothelioma (MPM) cells that lack type-I interferon (IFN-I) production or responsiveness. However, other cells in the tumor microenvironment (TME), such as myeloid cells, possess functional antiviral pathways. In this study, we aimed to characterize the interplay between MV and the myeloid cells in human MPM. We cocultured MPM cell lines with monocytes or macrophages and infected them with MV. We analyzed the transcriptome of each cell type and studied their secretion and phenotypes by high-dimensional flow cytometry. We also measured transgene expression using an MV encoding GFP (MV-GFP). We show that MPM cells drive the differentiation of monocytes into M2-like macrophages. These macrophages inhibit GFP expression in tumor cells harboring a defect in IFN-I production and a functional signaling downstream of the IFN-I receptor, while having minimal effects on GFP expression in tumor cells with defect of responsiveness to IFN-I. Interestingly, inhibition of the IFN-I signaling by ruxolitinib restores GFP expression in tumor cells. Upon MV infection, cocultured macrophages express antiviral pro-inflammatory genes and induce the expression of IFN-stimulated genes in tumor cells. MV also increases the expression of HLA and costimulatory molecules on macrophages and their phagocytic activity. Finally, MV induces the secretion of inflammatory cytokines, especially IFN-I, and PD-L1 expression in tumor cells and macrophages. These results show that macrophages reduce viral proteins expression in some MPM cell lines through their IFN-I production and generate a pro-inflammatory interplay that may stimulate the patient's anti-tumor immune response.

Keywords:  Measles virus; mesothelioma; oncolytic immunotherapy; tumor associated macrophages; type I interferon

DOI:  https://doi.org/10.1080/2162402X.2024.2377830
J Exp Clin Cancer Res. 2024 Jul 17. 43(1): 196

Plasmacytoid dendritic cells at the forefront of anti-cancer immunity: rewiring strategies for tumor microenvironment remodeling.

Matilde Monti, Giorgia Ferrari, Luisa Gazzurelli, Mattia Bugatti, Fabio Facchetti, William Vermi.

  Plasmacytoid dendritic cells (pDCs) are multifaceted immune cells executing various innate immunological functions. Their first line of defence consists in type I interferons (I-IFN) production upon nucleic acids sensing through endosomal Toll-like receptor (TLR) 7- and 9-dependent signalling pathways. Type I IFNs are a class of proinflammatory cytokines that have context-dependent functions on cancer immunosurveillance and immunoediting. In the last few years, different studies have reported that pDCs are also able to sense cytosolic DNA through cGAS-STING (stimulator of interferon genes) pathway eliciting a potent I-IFN production independently of TLR7/9. Human pDCs are also endowed with direct effector functions via the upregulation of TRAIL and production of granzyme B, the latter modulated by cytokines abundant in cancer tissues. pDCs have been detected in a wide variety of human malignant neoplasms, including virus-associated cancers, recruited by chemotactic stimuli. Although the role of pDCs in cancer immune surveillance is still uncompletely understood, their spontaneous activation has been rarely documented; moreover, their presence in the tumor microenvironment (TME) has been associated with a tolerogenic phenotype induced by immunosuppressive cytokines or oncometabolites. Currently tested treatment options can lead to pDCs activation and disruption of the immunosuppressive TME, providing a relevant clinical benefit. On the contrary, the antibody-drug conjugates targeting BDCA-2 on immunosuppressive tumor-associated pDCs (TA-pDCs) could be proposed as novel immunomodulatory therapies to achieve disease control in patients with advance stage hematologic malignancies or solid tumors. This Review integrate recent evidence on the biology of pDCs and their pharmacological modulation, suggesting their relevant role at the forefront of cancer immunity.

Keywords:  Cancer; Clinical trials; Cytotoxic function; Immune surveillance; Immunometabolism; Plasmacytoid dendritic cells; STING agonists; TLR7/9 agonists; Tumor microenvironment; Type I Interferon

DOI:  https://doi.org/10.1186/s13046-024-03121-9
Cell Oncol (Dordr). 2024 Jul 18.

Acidity and hypoxia of tumor microenvironment, a positive interplay in extracellular vesicle release by tumor cells.

Silvia Peppicelli, Lido Calorini, Francesca Bianchini, Laura Papucci, Lucia Magnelli, Elena Andreucci.

  The complex and continuously evolving features of the tumor microenvironment, varying between tumor histotypes, are characterized by the presence of host cells and tumor cells embedded in a milieu shaped by hypoxia and low pH, resulting from the frequent imbalance between vascularity and tumor cell proliferation. These microenvironmental metabolic stressors play a crucial role in remodeling host cells and tumor cells, contributing to the stimulation of cancer cell heterogeneity, clonal evolution, and multidrug resistance, ultimately leading to progression and metastasis. The extracellular vesicles (EVs), membrane-enclosed structures released into the extracellular milieu by tumor/host cells, are now recognized as critical drivers in the complex intercellular communication between tumor cells and the local cellular components in a hypoxic/acidic microenvironment. Understanding the intricate molecular mechanisms governing the interactions between tumor and host cells within a hypoxic and acidic microenvironment, triggered by the release of EVs, could pave the way for innovative strategies to disrupt the complex interplay of cancer cells with their microenvironment. This approach may contribute to the development of an efficient and safe therapeutic strategy to combat cancer progression. Therefore, we review the major findings on the release of EVs in a hypoxic/acidic tumor microenvironment to appreciate their role in tumor progression toward metastatic disease.

Keywords:  Acidosis; Cancer progression; Extracellular vesicles; Hypoxia; Tumor microenvironment

DOI:  https://doi.org/10.1007/s13402-024-00969-z
Scand J Immunol. 2023 Aug;98(2): e13273

The role of bone marrow microenvironment on CAR-T efficacy in haematologic malignancies.

Dandan Gao, Fei Hong, Aili He.

  In recent years, chimeric antigen receptor-T (CAR-T) cell therapy has emerged as a novel immunotherapy method. It has shown significant therapeutic efficacy in the treatment of haematological B cell malignancies. In particular, the CAR-T therapy targeting CD19 has yielded unprecedented efficacy for acute B-lymphocytic leukaemia (B-ALL) and non-Hodgkin's lymphoma (NHL). In haematologic malignancies, tumour stem cells are more prone to stay in the regulatory bone marrow (BM) microenvironment (called niches), which provides a protective environment against immune attack. However, how the BM microenvironment affects the anti-tumour efficacy of CAR-T cells and its underlying mechanism is worthy of attention. In this review, we discuss the role of the BM microenvironment on the efficacy of CAR-T in haematological malignancies and propose corresponding strategies to enhance the anti-tumour activity of CAR-T therapy.

Keywords:  CAR‐T cells; bone marrow microenvironment; haematologic malignancies

DOI:  https://doi.org/10.1111/sji.13273
Heliyon. 2024 Jun 30. 10(12): e33144

The role of CD8+ T-cells in colorectal cancer immunotherapy.

Tao He, Chencheng Hu, Shichao Li, Yao Fan, Fei Xie, Xin Sun, Qingfeng Jiang, Weidong Chen, Yingtian Jia, Wusheng Li.

  Immunotherapy has been an advanced and effective approach to treating various types of solid tumors in recent years, and the most successful strategy is immune checkpoint inhibitors (ICIs), which have shown beneficial effects in patients with colorectal cancer (CRC). Drug resistance to ICIs is usually associated with CD8+ T-cells targeting tumor antigens; thus, CD8+ T-cells play an important role in immunotherapy. Unfortunately, Under continuous antigen stimulation, tumor microenvironment(TME), hypoxia and other problems it leads to insufficient infiltration of CD8+ T-cells, low efficacy and mechanism exhaustion, which have become obstacles to immunotherapy. Thus, this article describes the relationship between CRC and the immune system, focuses on the process of CD8+ T-cells production, activation, transport, killing, and exhaustion, and expounds on related mechanisms leading to CD8+ T-cells exhaustion. Finally, this article summarizes the latest strategies and methods in recent years, focusing on improving the infiltration, efficacy, and exhaustion of CD8+ T-cells, which may help to overcome the barriers to immunotherapy.

Keywords:  CD8+ T-cells; Colorectal cancer; Immunotherapy; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/j.heliyon.2024.e33144
Transl Oncol. 2024 Jul 12. pii: S1936-5233(24)00182-7. [Epub ahead of print]47 102055

Non-genetic heterogeneity and immune subtyping in breast cancer: Implications for immunotherapy and targeted therapeutics.

Mudassir Hassan, Lütfi Tutar, Duygu Sari-Ak, Azhar Rasul, Ejaz Basheer, Yusuf Tutar.

  Breast cancer (BC) is a complex and multifactorial disease, driven by genetic alterations that promote tumor growth and progression. However, recent research has highlighted the importance of non-genetic factors in shaping cancer evolution and influencing therapeutic outcomes. Non-genetic heterogeneity refers to diverse subpopulations of cancer cells within breast tumors, exhibiting distinct phenotypic and functional properties. These subpopulations can arise through various mechanisms, including clonal evolution, genetic changes, epigenetic changes, and reversible phenotypic transitions. Although genetic and epigenetic changes are important points of the pathology of breast cancer yet, the immune system also plays a crucial role in its progression. In clinical management, histologic and molecular classification of BC are used. Immunological subtyping of BC has gained attention in recent years as compared to traditional techniques. Intratumoral heterogeneity revealed by immunological microenvironment (IME) has opened novel opportunities for immunotherapy research. This systematic review is focused on non-genetic variability to identify and interlink immunological subgroups in breast cancer. This review provides a deep understanding of adaptive methods adopted by tumor cells to withstand changes in the tumor microenvironment and selective pressure imposed by medications. These adaptive methods include alterations in drug targets, immune system evasion, activation of survival pathways, and alterations in metabolism. Understanding non-genetic heterogeneity is essential for the development of targeted therapies.

Keywords:  Breast cancer; Drug resistance; Immune subtypes; Non-genetic heterogeneity; Tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.tranon.2024.102055
Biochim Biophys Acta Rev Cancer. 2024 Jul 15. pii: S0304-419X(24)00086-6. [Epub ahead of print]1879(5): 189155

Targeting endothelial cell anergy to improve CAR T cell therapy for solid tumors.

Gabriela E Wachholz, Parvin Akbari, Elisabeth J M Huijbers, Prachi Jalan, Judy R van Beijnum, Arjan W Griffioen.

  Chimeric antigen receptor (CAR) T cell therapy presents significant results, especially for the treatment of hematologic malignancies. However, there are limitations and challenges to be overcome to achieve similar success for the treatment of solid tumors. These challenges involve selection of the target, infiltration into the tumor microenvironment and maintenance of functionality. The tumor vasculature is a major barrier for leukocytes to enter the tumor parenchyma. Due to the exposure of the vasculature to angiogenic growth factors during tumor progression, the endothelial cells become anergic to inflammatory cytokines, resulting in reduced leukocyte adhesion molecule expression. As such adhesion molecules are a prerequisite for leukocyte extravasation, endothelial cell anergy allows tumors to escape from endogenous immunity, as well as from cellular immunotherapies such as CAR T cells. Hence, overcoming endothelial cell anergy, e.g. through the administration of angiogenesis inhibitors, is believed to restore anti-tumor immunity. Concomitantly, both endogenous immune cells as well as cellular therapeutics such as CAR T cells can permeate into the tumor parenchyma. Here, we discuss how prior or concomitant treatment with an antiangiogenic drug can improve CAR T cell therapy, to become an attractive strategy for the treatment of solid tumors.

Keywords:  Angiogenesis; Anti-angiogenic therapy; Immunotherapy; Pro-angiogenic factors; Tumor endothelial cells; Tumor vasculature

DOI:  https://doi.org/10.1016/j.bbcan.2024.189155
Heliyon. 2024 Jun 30. 10(12): e32357

Glucocorticoids in lung cancer: Navigating the balance between immunosuppression and therapeutic efficacy.

Wenhui Xu, Jinghong Ye, Zhendong Cao, Yupei Zhao, Yimin Zhu, Lei Li.

  Glucocorticoids (GCs), a class of hormones secreted by the adrenal glands, are released into the bloodstream to maintain homeostasis and modulate responses to various stressors. These hormones function by binding to the widely expressed GC receptor (GR), thereby regulating a wide range of pathophysiological processes, especially in metabolism and immunity. The role of GCs in the tumor immune microenvironment (TIME) of lung cancer (LC) has been a focal point of research. As immunosuppressive agents, GCs exert a crucial impact on the occurrence, progression, and treatment of LC. In the TIME of LC, GCs act as a constantly swinging pendulum, simultaneously offering tumor-suppressive properties while diminishing the efficacy of immune-based therapies. The present study reviews the role and mechanisms of GCs in the TIME of LC.

Keywords:  Chronic airway inflammation; Glucocorticoids; Lung cancer; Tumor immunity; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.heliyon.2024.e32357
Nanomedicine (Lond). 2024 Jul 16. 1-20

Advancements in nanomedicine delivery systems: unraveling immune regulation strategies for tumor immunotherapy.

Yi Zhang, Xi Chen, Binbin Hu, Bingwen Zou, Yong Xu.

  This review highlights the significant role of nanodrug delivery systems (NDDS) in enhancing the efficacy of tumor immunotherapy. Focusing on the integration of NDDS with immune regulation strategies, it explores their transformative impacts on the tumor microenvironment and immune response dynamics. Key advancements include the optimization of drug delivery through NDDS, targeting mechanisms like immune checkpoint blockade and modulating the immunosuppressive tumor environment. Despite the progress, challenges such as limited clinical efficacy and complex manufacturing processes persist. The review emphasizes the need for further research to optimize these systems, potentially revolutionizing cancer treatment by improving delivery efficiency, reducing toxicity and overcoming immune resistance.

Keywords:  Immune evasion; Immunogenic cell death (ICD); Nano drug delivery systems (NDDS); Targeted drug delivery; Tumor immunotherapy

DOI:  https://doi.org/10.1080/17435889.2024.2374230
Magy Onkol. 2024 Jul 16. 68(2): 126-135

[Immunomodulation in the tumor microenvironment: Therapeutic potential of combined inhibition of tumor hypoxia and PD-1/ PD-L1].

Laura Svajda, Mihály Cserepes, Barbara Hegyi, Theodora Niczky, József Tóvári.

Tumor hypoxia plays an important role in controlling tumor progression through signaling pathways related to the transcription factor HIF-1. In addition to enhancing migration, promoting angiogenesis and regulating metabolism, the hypoxic environment also affects immune function. In this hypoxic microenvironment an immunosuppressive milieu is established, where HIF-1 upregulates the expression of PD-L1, a key regulator of the immune response. We have found that elevated expression of PD-L1 correlates with increased HIF-1 levels in cancer cell lines and clinical samples. Thus, the co-inhibition of HIF-1 and PD-1/PD-L1 offers promising therapeutic possibilities. In this review we have examined the limitations of HIF-1 and PD-1/PD-L1 inhibition as monotherapy, explored their combined benefits and evaluated the feasibility of targeting PD-L1 with HIF-1 inhibitors.
Nano Lett. 2024 Jul 15.

Reprogramming Tumor-Associated Macrophages with a Se-Based Core-Satellite Nanoassembly to Enhance Cancer Immunotherapy.

Xia Zhang, Guocheng Li, Jiaqi Yin, Wei Pan, Yanhua Li, Na Li, Bo Tang.

  Tumor-associated macrophages (TAMs), as the most prevalent immune cells in the tumor microenvironment, play a pivotal role in promoting tumor development through various signaling pathways. Herein, we have engineered a Se@ZIF-8 core-satellite nanoassembly to reprogram TAMs, thereby enhancing immunotherapy outcomes. When the nanoassembly reaches the tumor tissue, selenium nanoparticles and Zn2+ are released in response to the acidic tumor microenvironment, resulting in a collaborative effort to promote the production of reactive oxygen species (ROS). The generated ROS, in turn, activate the nuclear factor κB (NF-κB) signaling pathway, driving the repolarization of TAMs from M2-type to M1-type, effectively eliminating cancer cells. Moreover, the nanoassembly can induce the immunogenic death of cancer cells through excess ROS to expose calreticulin and boost macrophage phagocytosis. The Se@ZIF-8 core-satellite nanoassembly provides a potential paradigm for cancer immunotherapy by reversing the immunosuppressive microenvironment.

Keywords:  cancer; core−satellite nanoassembly; immunotherapy; reactive oxygen species; tumor-associated macrophages

DOI:  https://doi.org/10.1021/acs.nanolett.4c02657
Cell Oncol (Dordr). 2024 Jul 15.

Panoramic tumor microenvironment in pancreatic ductal adenocarcinoma.

Xiaoying Li, Wanting Hou, Chaoxin Xiao, Heqi Yang, Chengjian Zhao, Dan Cao.

  Pancreatic ductal adenocarcinoma (PDAC) is notorious for its resistance to various treatment modalities. The genetic heterogeneity of PDAC, coupled with the presence of a desmoplastic stroma within the tumor microenvironment (TME), contributes to an unfavorable prognosis. The mechanisms and consequences of interactions among different cell types, along with spatial variations influencing cellular function, potentially play a role in the pathogenesis of PDAC. Understanding the diverse compositions of the TME and elucidating the functions of microscopic neighborhoods may contribute to understanding the immune microenvironment status in pancreatic cancer. As we delve into the spatial biology of the microscopic neighborhoods within the TME, aiding in deciphering the factors that orchestrate this intricate ecosystem. This overview delineates the fundamental constituents and the structural arrangement of the PDAC microenvironment, highlighting their impact on cancer cell biology.

Keywords:  Pancreatic ductal adenocarcinoma; Spatial perspective; Tumor microenvironment

DOI:  https://doi.org/10.1007/s13402-024-00970-6
Tissue Cell. 2024 Jul 09. pii: S0040-8166(24)00171-X. [Epub ahead of print]89 102470

The role of tissue-derived extracellular vesicles in tumor microenvironment.

Jin Lin, Wan Lu, Bo Huang, Weiming Yang, Xiaozhong Wang.

  The tumor microenvironment (TME) is a highly heterogeneous ecosystem that plays critical roles in the initiation, progression, invasion, and metastasis of cancers. Extracellular vesicles (EVs), as emerging components of the host-tumor communication, are lipid-bilayer membrane structures that are secreted by most cell types into TEM and increasingly recognized as critical elements that regulate the interaction between tumor cells and their surroundings. They contain a variety of bioactive molecules, such as proteins, nucleic acids, and lipids, and participate in various pathophysiological processes while regulating intercellular communication. While many studies have focused on the EVs derived from different body fluids or cell culture supernatants, the direct isolation of tissue-derived EVs (Ti-EVs) has garnered more attention due to the advantages of tissue specificity and accurate reflection of tissue microenvironment. In this review, we summarize the protocol for isolating Ti-EVs from different tissue interstitium, discuss the role of tumor-derived and adipose tissue-derived Ti-EVs in regulating TME. In addition, we sum up the latest application of Ti-EVs as potential biomarkers for cancer diseases.

Keywords:  Extracellular vesicles; Research progress; Tissue-derived extracellular vesicles; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.tice.2024.102470
PeerJ. 2024 ;12 e17667

The potential role of CD8+ cytotoxic T lymphocytes and one branch connected with tissue-resident memory in non-luminal breast cancer.

Ziqi Zhao, Xinyu Ma, Zhengang Cai.

  Advances in understanding the pathological mechanisms of breast cancer have resulted in the emergence of novel therapeutic strategies. However, triple-negative breast cancer (TNBC), a molecular subtype of breast cancer with a poor prognosis, lacks classical and general therapeutic targets, hindering the clinical application of several therapies to breast cancer. As insights into the unique immunity and molecular mechanisms of TNBC have become more extensive, immunotherapy has gradually become a valuable complementary approach to classical radiotherapy and chemotherapy. CD8+ cells are significant actors in the tumor immunity cycle; thus, research on TNBC immunotherapy is increasingly focused in this direction. Recently, CD8+ tissue-resident memory (TRM) cells, a subpopulation of CD8+ cells, have been explored in relation to breast cancer and found to seemingly play an undeniably important role in tumor surveillance and lymphocytic infiltration. In this review, we summarize the recent advances in the mechanisms and relative targets of CD8+ T cells, and discuss the features and potential applications of CD8+ TRM cells in non-luminal breast cancer immunotherapy.

Keywords:  Breast cancer; CD8+ T cells; Immunotherapy; Tissue-resident memory T cell; Triple negative breast cancer

DOI:  https://doi.org/10.7717/peerj.17667
bioRxiv. 2024 Jul 04. pii: 2024.07.02.601733. [Epub ahead of print]

FABP4-mediated lipid accumulation and lipolysis in tumor associated macrophages promote breast cancer metastasis.

Matthew Yorek, Xingshan Jiang, Shanshan Liu, Jiaqing Hao, Jianyu Yu, Anthony Avellino, Zhanxu Liu, Melissa Curry, Henry Keen, Jianqiang Shao, Anand Kanagasabapathy, Maiying Kong, Yiqin Xiong, Edward R Sauter, Sonia L Sugg, Bing Li.

A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cells, which promotes cancer cell migration in vitro and metastasis in vivo . Notably, a deficiency of FABP4 in macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer.
Graphic Abstract:
Highlights: Unlike saturated fatty acids, unsaturated fatty acids preferentially promote lipid droplet formation in macrophages.Unsaturated fatty acids activate the FABP4/CEBPα axis for neutral lipid biosynthesis in macrophagesDeficiency of FABP4 compromised unsaturated fatty acid-mediated lipid accumulation and utilization in macrophagesFABP4-mediated lipid metabolism in macrophages contributes to breast cancer metastasis.

DOI: https://doi.org/10.1101/2024.07.02.601733
Biochim Biophys Acta Rev Cancer. 2024 Jul 15. pii: S0304-419X(24)00085-4. [Epub ahead of print]1879(5): 189154

Reactive oxygen species of tumor microenvironment: Harnessing for immunogenic cell death.

RamaRao Malla, Seema Kumari, Swapna Priya Ganji, Mundla Srilatha, Haasita Reddy Nellipudi, Ganji Purnachandra Nagaraju.

  The tumor microenvironment (TME) is a dynamic and complex system that undergoes continuous changes in its network architecture, notably affecting redox homeostasis. These alterations collectively shape a diverse ecosystem actively supporting tumor progression by influencing the cellular and molecular components of the TME. Despite the remarkable clinical advancements in cancer immunotherapy, its spectrum of clinical utility is limited by the altered TME and inadequate tumor immunogenicity. Recent studies have revealed that some conventional and targeted therapy strategies can augment the efficacy of immunotherapy even in patients with less immunogenic solid tumors. These strategies provoke immunogenic cell death (ICD) through the ROS-dependent liberation of damage-associated molecular patterns (DAMPs). These DAMPs recognize and bind with Pattern Recognition Receptors (PRRs) on immune cells, activating and maturing defense cells, ultimately leading to a robust antitumor immune response. The present review underscores the pivotal role of redox homeostasis in orchestrating the transition of TME from a cold to a hot phenotype and the ROS-ICD axis in immune response induction. Additionally, it provides up-to-date insights into strategies that leverage ROS generation to induce ICD. The comprehensive analysis aims to develop ROS-based effective cancer immunotherapies for less immunogenic tumors.

Keywords:  Cancer immunotherapy; Damage-associated molecular patterns; Immunogenic cell death; Redox homeostasis; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2024.189154