bims-flamet 2024-05-19 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–05–19
thirty-two papers selected by
Peio Azcoaga, Biodonostia HRI

Macrophages Orchestrate the Liver Tumor Microenvironment.
Interleukine-10 in ovarian cancer.
The Tumor Stroma of Squamous Cell Carcinoma: A Complex Environment That Fuels Cancer Progression.
New roles of tumor-derived exosomes in tumor microenvironment.
Breast cancer-on-chip for patient-specific efficacy and safety testing of CAR-T cells.
CPT1C-positive cancer-associated fibroblast facilitates immunosuppression through promoting IL-6-induced M2-like phenotype of macrophage.
Hypoxic tumor microenvironment: Destroyer of natural killer cell function.
Host-derived Interleukin 1α induces an immunosuppressive tumor microenvironment via regulating monocyte-to-macrophage differentiation.
Emerging Trends in Gastrointestinal Cancer Targeted Therapies: Harnessing Tumor Microenvironment, Immune Factors, and Metabolomics Insights.
Heterocellular Adhesion in Cancer Invasion and Metastasis: Interactions between Cancer Cells and Cancer-Associated Fibroblasts.
Ganoderma lucidum spores-derived particulate β-glucan treatment improves antitumor response by regulating myeloid-derived suppressor cells in triple-negative breast cancer.
Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response.
Posttranslational protein modifications as gatekeepers of cancer immunogenicity.
Characterization of innate lymphoid cell subsets infiltrating melanoma and epithelial ovarian tumors.
Immunometabolism in cancer: basic mechanisms and new targeting strategy.
GPC3-targeted CAR-T cells expressing GLUT1 or AGK exhibit enhanced antitumor activity against hepatocellular carcinoma.
Targeting neutrophil elastase is a promising direction for future cancer treatment.
Arming Vδ2 T cells with chimeric antigen receptors to combat cancer.
Granzyme B-activated IL18 potentiates αβ and γδ CAR T-cell immunotherapy in a tumor-dependent manner.
Enhanced systemic antitumor efficacy of PD-1/PD-L1 blockade with immunological response induced by photodynamic therapy.
Tumor-associated NK cells drive MDSC-mediated tumor immune tolerance through the IL-6/STAT3 axis.
Immune Checkpoint Inhibitors: A Narrative Review on PD-1/PD-L1 Blockade Mechanism, Efficacy, and Safety Profile in Treating Malignancy.
The biological behavior and clinical outcome of pituitary adenoma are affected by the microenvironment.
Heterogeneity of myeloid cells in common cancers: Single cell insights and targeting strategies.
Interleukin-12 in multimodal tumor therapies for induction of anti-tumor immunity.
BCKDK Modification Enhances the Anticancer Efficacy of CAR-T Cells by Reprogramming Branched Chain Amino Acid Metabolism.
The role of proinflammatory cytokines and CXC chemokines (CXCL1-CXCL16) in the progression of prostate cancer: insights on their therapeutic management.
Predictive and Prognostic Relevance of Tumor-Infiltrating Immune Cells: Tailoring Personalized Treatments against Different Cancer Types.
PAK1 inhibition increases TRIM21-induced PD-L1 degradation and enhances responses to anti-PD-1 therapy in pancreatic cancer.
Metastasis and angiogenesis in cervical cancer: key aspects of purinergic signaling in platelets and possible therapeutic targets.
IL-3-driven T cell-basophil crosstalk enhances antitumor immunity.
The role of the microscopic world: Exploring the role and potential of intratumoral microbiota in cancer immunotherapy.

Cancers (Basel). 2024 May 04. pii: 1772. [Epub ahead of print]16(9):

Macrophages Orchestrate the Liver Tumor Microenvironment.

Valeria Quaranta, Costanza Ballarò, Gianluigi Giannelli.

  Liver cancer is one of the leading causes of cancer-related mortality. Hepatocellular carcinoma and cholangiocarcinoma are the most common types, and despite numerous advances, therapeutic options still remain poor for these cancer patients. Tumor development and progression strictly depend on a supportive tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are the most abundant immune cells population within a tumorigenic liver; they sustain cancer cells' growth and invasiveness, and their presence is correlated with a poor prognosis. Furthermore, TAM cross-talk with cells and components of the TME promotes immunosuppression, a desmoplastic response, and angiogenesis. In this review, we summarize the latest advances in understanding TAM heterogeneity and function, with a particular focus on TAM modulation of the TME. We also discuss the potential of targeting macrophage subpopulations and how this is now being exploited in current clinical trials for the treatment of liver cancer.

Keywords:  cholangiocarcinoma; hepatocellular carcinoma; liver cancer; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3390/cancers16091772
Chin Clin Oncol. 2024 May 09. pii: cco-23-135. [Epub ahead of print]

Interleukine-10 in ovarian cancer.

Gabriel Levin, Walter Henry Gotlieb.

  Interleukins serve as communicating molecules between cells, mediating key interactions in the tumor microenvironment (TME) between immune cells and non-immune cells. Interleukin-10 (IL-10), a multifunctional cytokine with multiple properties, has been extensively studied in various aspects of immunology and cancer biology. IL-10 is pleiotropic, promotes cytotoxicity, yet inhibits antitumorresponses. In recent years, the role of IL-10 in ovarian cancer (OC) progression and treatment has gained significant scientific attention, elucidating the signaling pathways triggered by IL-10 action. OC, the leading cause of gynecologic cancer-related deaths, is characterized by ascites, which hosts an intricate TME that is not responsive to treatment by immune checkpoint inhibition. IL-10, known for its immunosuppressive and anti-inflammatory properties, plays a complex role in OC progression, immune modulation, and therapeutic response and has a potential therapeutic property as a target and as an effector. As the literature of basic science research studying the role of IL-10 in the TME of OC scopes a few decades and some data is contrasting, it is important to review the literature and provide concise input derived from it. This review aims to provide a comprehensive overview of the current understanding of IL-10 in OC, highlighting its influence on tumor growth, immune evasion, and potential as a therapeutic target.

Keywords:  Cancer immunotherapy; cytokines; interleukin-10 (IL-10); ovarian cancer (OC); tumor microenvironment (TME)

DOI:  https://doi.org/10.21037/cco-23-135
Cancers (Basel). 2024 Apr 29. pii: 1727. [Epub ahead of print]16(9):

The Tumor Stroma of Squamous Cell Carcinoma: A Complex Environment That Fuels Cancer Progression.

Alexandra Buruiană, Bogdan-Alexandru Gheban, Ioana-Andreea Gheban-Roșca, Carmen Georgiu, Doința Crișan, Maria Crișan.

  The tumor microenvironment (TME), a complex assembly of cellular and extracellular matrix (ECM) components, plays a crucial role in driving tumor progression, shaping treatment responses, and influencing metastasis. This narrative review focuses on the cutaneous squamous cell carcinoma (cSCC) tumor stroma, highlighting its key constituents and their dynamic contributions. We examine how significant changes within the cSCC ECM-specifically, alterations in fibronectin, hyaluronic acid, laminins, proteoglycans, and collagens-promote cancer progression, metastasis, and drug resistance. The cellular composition of the cSCC TME is also explored, detailing the intricate interplay of cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), endothelial cells, pericytes, adipocytes, and various immune cell populations. These diverse players modulate tumor development, angiogenesis, and immune responses. Finally, we emphasize the TME's potential as a therapeutic target. Emerging strategies discussed in this review include harnessing the immune system (adoptive cell transfer, checkpoint blockade), hindering tumor angiogenesis, disrupting CAF activity, and manipulating ECM components. These approaches underscore the vital role that deciphering TME interactions plays in advancing cSCC therapy. Further research illuminating these complex relationships will uncover new avenues for developing more effective treatments for cSCC.

Keywords:  cutaneous squamous cell carcinoma; extracellular matrix; immune cells; stroma; therapy; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers16091727
Chin J Cancer Res. 2024 Apr 30. 36(2): 151-166

New roles of tumor-derived exosomes in tumor microenvironment.

Shiqian Chen, Jinzhe Sun, Huan Zhou, Hongbin Lei, Dan Zang, Jun Chen.

  Throughout tumorigenesis, the co-evolution of tumor cells and their surrounding microenvironment leads to the development of malignant phenotypes. Cellular communication within the tumor microenvironment (TME) plays a critical role in influencing various aspects of tumor progression, including invasion and metastasis. The release of exosomes, a type of extracellular vesicle, by most cell types in the body, is an essential mediator of intercellular communication. A growing body of research indicates that tumor-derived exosomes (TDEs) significantly expedite tumor progression through multiple mechanisms, inducing epithelial-mesenchymal transition and macrophage polarization, enhancing angiogenesis, and aiding in the immune evasion of tumor cells. Herein, we describe the formation and characteristics of the TME, and summarize the contents of TDEs and their diverse functions in modulating tumor development. Furthermore, we explore potential applications of TDEs in tumor diagnosis and treatment.

Keywords:  Tumor-derived exosomes; diagnosis; treatment; tumor microenvironment; tumorigenesis

DOI:  https://doi.org/10.21147/j.issn.1000-9604.2024.02.05
Cell Stem Cell. 2024 May 10. pii: S1934-5909(24)00145-0. [Epub ahead of print]

Breast cancer-on-chip for patient-specific efficacy and safety testing of CAR-T cells.

Tengku Ibrahim Maulana, Claudia Teufel, Madalena Cipriano, Julia Roosz, Lisa Lazarevski, Francijna E van den Hil, Lukas Scheller, Valeria Orlova, André Koch, Michael Hudecek, Miriam Alb, Peter Loskill.

  Physiologically relevant human models that recapitulate the challenges of solid tumors and the tumor microenvironment (TME) are highly desired in the chimeric antigen receptor (CAR)-T cell field. We developed a breast cancer-on-chip model with an integrated endothelial barrier that enables the transmigration of perfused immune cells, their infiltration into the tumor, and concomitant monitoring of cytokine release during perfused culture over a period of up to 8 days. Here, we exemplified its use for investigating CAR-T cell efficacy and the ability to control the immune reaction with a pharmacological on/off switch. Additionally, we integrated primary breast cancer organoids to study patient-specific CAR-T cell efficacy. The modular architecture of our tumor-on-chip paves the way for studying the role of other cell types in the TME and thus provides the potential for broad application in bench-to-bedside translation as well as acceleration of the preclinical development of CAR-T cell products.

Keywords:  CAR-T cells; cancer; cancer immunotherapy; cancer model; organ-on-chip; solid tumor; tumor immunology; tumor microenvironment

DOI:  https://doi.org/10.1016/j.stem.2024.04.018
Oncoimmunology. 2024 ;13(1): 2352179

CPT1C-positive cancer-associated fibroblast facilitates immunosuppression through promoting IL-6-induced M2-like phenotype of macrophage.

Rongyuan Wei, Junquan Song, Hongda Pan, Xiaowen Liu, Jianpeng Gao.

  Cancer-associated fibroblasts (CAFs) exhibit remarkable phenotypic heterogeneity, with specific subsets implicated in immunosuppression in various malignancies. However, whether and how they attenuate anti-tumor immunity in gastric cancer (GC) remains elusive. CPT1C, a unique isoform of carnitine palmitoyltransferase pivotal in regulating fatty acid oxidation, is briefly indicated as a protumoral metabolic mediator in the tumor microenvironment (TME) of GC. In the present study, we initially identified specific subsets of fibroblasts exclusively overexpressing CPT1C, hereby termed them as CPT1C+CAFs. Subsequent findings indicated that CPT1C+CAFs fostered a stroma-enriched and immunosuppressive TME as they correlated with extracellular matrix-related molecular features and enrichment of both immunosuppressive subsets, especially M2-like macrophages, and multiple immune-related pathways. Next, we identified that CPT1C+CAFs promoted the M2-like phenotype of macrophage in vitro. Bioinformatic analyses unveiled the robust IL-6 signaling between CPT1C+CAFs and M2-like phenotype of macrophage and identified CPT1C+CAFs as the primary source of IL-6. Meanwhile, suppressing CPT1C expression in CAFs significantly decreased IL-6 secretion in vitro. Lastly, we demonstrated the association of CPT1C+CAFs with therapeutic resistance. Notably, GC patients with high CPT1C+CAFs infiltration responded poorly to immunotherapy in clinical cohort. Collectively, our data not only present the novel identification of CPT1C+CAFs as immunosuppressive subsets in TME of GC, but also reveal the underlying mechanism that CPT1C+CAFs impair tumor immunity by secreting IL-6 to induce the immunosuppressive M2-like phenotype of macrophage in GC.

Keywords:  Carnitine palmitoyltransferase 1C; M2-like macrophage; cancer-associated fibroblast; gastric cancer; immunosuppression; interleukin 6

DOI:  https://doi.org/10.1080/2162402X.2024.2352179
Chin J Cancer Res. 2024 Apr 30. 36(2): 138-150

Hypoxic tumor microenvironment: Destroyer of natural killer cell function.

Yongfei Zhang, Feifei Guo, Yufeng Wang.

  In recent years, immunotherapy has made remarkable progress in treating certain tumors and hematological malignancies. However, the efficacy of natural killer (NK) cells, which are an important subset of innate lymphocytes used in anticancer immunotherapy, remains limited. Hypoxia, a critical characteristic of the tumor microenvironment (TME), is involved in tumor development and resistance to radiotherapy, chemotherapy, and immunotherapy. Moreover, hypoxia contributes to the impairment of NK cell function and may be a significant factor that limits their therapeutic effects. Targeted hypoxia therapy has emerged as a promising research area for enhancing the efficacy of NK cell therapy. Therefore, understanding how the hypoxic TME influences NK cell function is crucial for improving antitumor treatment outcomes.

Keywords:  Hypoxia; NK cell; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.21147/j.issn.1000-9604.2024.02.04
bioRxiv. 2024 May 05. pii: 2024.05.03.592354. [Epub ahead of print]

Host-derived Interleukin 1α induces an immunosuppressive tumor microenvironment via regulating monocyte-to-macrophage differentiation.

Manikanda Raja Keerthi Raja, Gourab Gupta, Grace Atkinson, Katie Kathrein, Alissa Armstrong, Michael Gower, Igor Roninson, Eugenia Broude, Menqiang Chen, Hao Ji, Chang-Uk Lim, Hongjun Wang, Daping Fan, Peisheng Xu, Jie Li, Gang Zhou, Hexin Chen.

Tumor-associated macrophages exhibit high heterogeneity and contribute to the establishment of an immunosuppressive tumor microenvironment (TME). Although numerous studies have demonstrated that extracellular factors promote macrophage proliferation and polarization, the regulatory mechanisms governing the differentiation process to generate phenotypically, and functionally diverse macrophage subpopulations remain largely unexplored. In this study, we examined the influence of interleukin 1α (IL-1α) on the development of an immunosuppressive TME using orthotopic transplantation murine models of breast cancer. Deletion of host Il1α led to the rejection of inoculated congenic tumors. Single-cell sequencing analysis revealed that CX3CR1+ macrophage cells were the primary sources of IL-1α in the TME. The absence of IL-1α reprogrammed the monocyte-to-macrophage differentiation process within the TME, characterized by a notable decrease in the subset of CX3CR+ ductal-like macrophages and an increase in iNOS-expressing inflammatory cells. Comparative analysis of gene signatures in both human and mouse macrophage subsets suggested that IL-1α deficiency shifted the macrophage polarization from M2 to M1 phenotypes, leading to enhanced cytotoxic T lymphocyte activity in the TME. Importantly, elevated levels of IL-1α in human cancers were associated with worse prognosis following immunotherapy. These findings underscore the pivotal role of IL-1α in shaping an immune-suppressive TME through the regulation of macrophage differentiation and activity, highlighting IL-1α as a potential target for breast cancer treatment.
Teaser: Interleukin 1α dictates macrophage behavior, influencing an immunosuppressive microenvironment in breast cancer, suggesting it as a treatment target.

DOI: https://doi.org/10.1101/2024.05.03.592354
Gastroenterology. 2024 May 15. pii: S0016-5085(24)04917-5. [Epub ahead of print]

Emerging Trends in Gastrointestinal Cancer Targeted Therapies: Harnessing Tumor Microenvironment, Immune Factors, and Metabolomics Insights.

Sanchita Rauth, Mokenge Malafa, Moorthy P Ponnusamy, Surinder K Batra.

  Gastrointestinal (GI) cancers are the leading cause of new cancer cases and cancer-related deaths worldwide. The treatment strategies for patients with GI tumors have focused on oncogenic molecular profiles associated with tumor cells. Recent evidence demonstrated that tumor cell functions are modulated by its microenvironment, compromising fibroblasts, ECMs, microbiome, immune cells, and the enteric nervous system. Along with the TME components, alterations in key metabolic pathways have emerged as a hallmark of tumor cells. From these perspectives, this review will highlight the functions of different cellular components of the GI tumor microenvironment (TME) and their implications for treatment. Furthermore, we discuss the major metabolic reprogramming in GI tumor cells and how understanding metabolic rewiring could lead to new therapeutic strategies. Finally, we briefly summarize the targeted agents currently being studied in GI cancers. Understanding the complex interplay between tumor cell-intrinsic and cell-extrinsic during tumor progression is critical for developing new therapeutic strategies.

Keywords:  Gastrointestinal cancers; Immune landscapes; Metabolic reprogramming; Targeted therapies; Tumor microenvironment

DOI:  https://doi.org/10.1053/j.gastro.2024.05.005
Cancers (Basel). 2024 Apr 24. pii: 1636. [Epub ahead of print]16(9):

Heterocellular Adhesion in Cancer Invasion and Metastasis: Interactions between Cancer Cells and Cancer-Associated Fibroblasts.

Hideki Yamaguchi, Makoto Miyazaki.

  Cancer invasion is a requisite for the most malignant progression of cancer, that is, metastasis. The mechanisms of cancer invasion were originally studied using in vitro cell culture systems, in which cancer cells were cultured using artificial extracellular matrices (ECMs). However, conventional culture systems do not precisely recapitulate in vivo cancer invasion because the phenotypes of cancer cells in tumor tissues are strongly affected by the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the TME and accelerate cancer progression through invasion, metastasis, therapy resistance, and immune suppression. Thus, the reciprocal interactions between CAFs and cancer cells have been extensively studied, leading to the identification of factors that mediate cellular interactions, such as growth factors, cytokines, and extracellular vesicles. In addition, the importance of direct heterocellular adhesion between cancer cells and CAFs in cancer progression has recently been elucidated. In particular, CAFs are directly associated with cancer cells, allowing them to invade the ECM and metastasize to distant organs. In this review, we summarize the recent progress in understanding the molecular and cellular mechanisms of the direct heterocellular interaction in CAF-led cancer invasion and metastasis, with an emphasis on gastric cancer.

Keywords:  cancer-associated fibroblast; extracellular matrix; heterocellular adhesion; invasion; metastasis

DOI:  https://doi.org/10.3390/cancers16091636
Int J Biol Macromol. 2024 May 03. pii: S0141-8130(24)02754-5. [Epub ahead of print] 131949

Ganoderma lucidum spores-derived particulate β-glucan treatment improves antitumor response by regulating myeloid-derived suppressor cells in triple-negative breast cancer.

Yang Bu, Qian Liu, Yongjie Shang, Zhenzhen Zhao, Haonan Sun, Feifei Chen, Qian Ma, Jie Song, Li Cui, E Sun, Yi Luo, Luan Shu, Haibo Jing, Xiaobin Tan.

  Granular β-1,3-glucan extracted from the wall of Ganoderma lucidum spores, named GPG, is a bioregulator. In this study, we investigated the structural, thermal, and other physical properties of GPG. We determined whether GPG ameliorated immunosuppression caused by Gemcitabine (GEM) chemotherapy. Triple-negative breast cancer mice with GPG combined with GEM treatment had reduced tumor burdens. In addition, GEM treatment alone altered the tumor microenvironment(TME), including a reduction in antitumor T cells and a rise in myeloid-derived suppressor cells (MDSC) and regulatory T cells (Tregs). However, combined GPG treatment reversed the tumor immunosuppressive microenvironment induced by GEM. GPG inhibited bone marrow (BM)-derived MDSC differentiation and reversed MDSC expansion induced by conditioned medium (CM) in GEM-treated E0771 cells through a Dectin-1 pathway. In addition, GPG downgraded PD-L1 and IDO1 expression on MDSC while boosting MHC-II, CD86, TNF-α, and IL-6 expression. In conclusion, this study demonstrated that GPG could alleviate the adverse effects induced by GEM chemotherapy by regulating TME.

Keywords:  Beta-glucan; Chemotherapy; Triple-negative breast cancer (TNBC)

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.131949
Cell Rep. 2024 May 16. pii: S2211-1247(24)00564-3. [Epub ahead of print]43(5): 114236

Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response.

Chen Lior, Debra Barki, Coral Halperin, Christine A Iacobuzio-Donahue, David Kelsen, Ruth Scherz- Shouval.

  The tumor microenvironment (TME) presents cells with challenges such as variable pH, hypoxia, and free radicals, triggering stress responses that affect cancer progression. In this study, we examine the stress response landscape in four carcinomas-breast, pancreas, ovary, and prostate-across five pathways: heat shock, oxidative stress, hypoxia, DNA damage, and unfolded protein stress. Using a combination of experimental and computational methods, we create an atlas of stress responses across various types of carcinomas. We find that stress responses vary within the TME and are especially active near cancer cells. Focusing on the non-immune stroma we find, across tumor types, that NRF2 and the oxidative stress response are distinctly activated in immune-regulatory cancer-associated fibroblasts and in a unique subset of cancer-associated pericytes. Our study thus provides an interactome of stress responses in cancer, offering ways to intersect survival pathways within the tumor, and advance cancer therapy.

Keywords:  CP: Cancer; NRF2; cancer; cancer-associated fibroblasts; fibroblasts; oxidative stress; pericytes; scRNA-seq; stress responses; stroma; tumor microenvrionemnt

DOI:  https://doi.org/10.1016/j.celrep.2024.114236
J Clin Invest. 2024 May 15. pii: e180914. [Epub ahead of print]134(10):

Posttranslational protein modifications as gatekeepers of cancer immunogenicity.

Emanuela Marchese, Shadmehr Demehri.

Triple-negative breast cancer (TNBC) presents a formidable challenge in oncology due to its aggressive phenotype and the immunosuppressive nature of its tumor microenvironment (TME). In this issue of the JCI, Zhu, Banerjee, and colleagues investigated the potential of targeting the OTU domain-containing protein 4 (OTUD4)/CD73 axis to mitigate immunosuppression in TNBC. They identified elevated CD73 expression as a hallmark of immunosuppression in TNBC. Notably, the CD73 expression was regulated by OTUD4-mediated posttranslational modifications. Using ST80, a pharmacologic inhibitor of OTUD4, the authors demonstrated the restoration of cytotoxic T cell function and enhanced efficacy of anti-PD-L1 therapy in preclinical models. These findings underscore the therapeutic potential of targeting the OTUD4/CD73 axis in TNBC.

DOI: https://doi.org/10.1172/JCI180914
Oncoimmunology. 2024 ;13(1): 2349347

Characterization of innate lymphoid cell subsets infiltrating melanoma and epithelial ovarian tumors.

Douglas C Chung, Maryam Ghaedi, Kathrin Warner, Azin Sayad, Samuel D Saibil, Marcus Q Bernardini, Blaise A Clarke, Patricia A Shaw, Marcus O Butler, Alexandra Easson, Sorana Morrissy, Ben X Wang, Linh Nguyen, Pamela S Ohashi, Nicolas Jacquelot.

  The innate lymphoid cell (ILC) family is composed of heterogeneous innate effector and helper immune cells that preferentially reside in tissues where they promote tissue homeostasis. In cancer, they have been implicated in driving both pro- and anti-tumor responses. This apparent dichotomy highlights the need to better understand differences in the ILC composition and phenotype within different tumor types that could drive seemingly opposite anti-tumor responses. Here, we characterized the frequency and phenotype of various ILC subsets in melanoma metastases and primary epithelial ovarian tumors. We observed high PD-1 expression on ILC subsets isolated from epithelial ovarian tumor samples, while ILC populations in melanoma samples express higher levels of LAG-3. In addition, we found that the frequency of cytotoxic ILCs and NKp46+ILC3 in tumors positively correlates with monocytic cells and conventional type 2 dendritic cells, revealing potentially new interconnected immune cell subsets in the tumor microenvironment. Consequently, these observations may have direct relevance to tumor microenvironment composition and how ILC subset may influence anti-tumor immunity.

Keywords:  Epithelial ovarian cancer; LAG-3; NK cells; PD-1; T cells; innate lymphoid cells; melanoma; myeloid cells

DOI:  https://doi.org/10.1080/2162402X.2024.2349347
Cell Death Discov. 2024 May 16. 10(1): 236

Immunometabolism in cancer: basic mechanisms and new targeting strategy.

Ranran Su, Yingying Shao, Manru Huang, Donghui Liu, Haiyang Yu, Yuling Qiu.

Maturing immunometabolic research empowers immune regulation novel approaches. Progressive metabolic adaptation of tumor cells permits a thriving tumor microenvironment (TME) in which immune cells always lose the initial killing capacity, which remains an unsolved dilemma even with the development of immune checkpoint therapies. In recent years, many studies on tumor immunometabolism have been reported. The development of immunometabolism may facilitate anti-tumor immunotherapy from the recurrent crosstalk between metabolism and immunity. Here, we discuss clinical studies of the core signaling pathways of immunometabolism and their inhibitors or agonists, as well as the specific functions of these pathways in regulating immunity and metabolism, and discuss some of the identified immunometabolic checkpoints. Understanding the comprehensive advances in immunometabolism helps to revise the status quo of cancer treatment. An overview of the new landscape of immunometabolism. The PI3K pathway promotes anabolism and inhibits catabolism. The LKB1 pathway inhibits anabolism and promotes catabolism. Overactivation of PI3K/AKT/mTOR pathway and IDO, IL4I1, ACAT, Sirt2, and MTHFD2 promote immunosuppression of TME formation, as evidenced by increased Treg and decreased T-cell proliferation. The LKBI-AMPK pathway promotes the differentiation of naive T cells to effector T cells and memory T cells and promotes anti-tumor immunity in DCs.

DOI: https://doi.org/10.1038/s41420-024-02006-2
Acta Pharmacol Sin. 2024 May 15.

GPC3-targeted CAR-T cells expressing GLUT1 or AGK exhibit enhanced antitumor activity against hepatocellular carcinoma.

Rui-Xin Sun, Yi-Fan Liu, Yan-Sha Sun, Min Zhou, Yi Wang, Bi-Zhi Shi, Hua Jiang, Zong-Hai Li.

  Chimeric antigen receptor-expressing T (CAR-T) cells induce robust antitumor responses in patients with hematologic malignancies. However, CAR-T cells exhibit only limited efficacy against solid tumors such as hepatocellular carcinoma (HCC), partially due to their limited expansion and persistence. CD8+ T cells, as key components of the adaptive immune response, play a central role in antitumor immunity. Aerobic glycolysis is the main metabolic feature of activated CD8+ T cells. In the tumor microenvironment, however, the uptake of large amounts of glucose by tumor cells and other immunosuppressive cells can impair the activation of T cells. Only when tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment have a glycolytic advantage might the effector function of T cells be activated. Glucose transporter type 1 (GLUT1) and acylglycerol kinase (AGK) can boost glycolytic metabolism and activate the effector function of CD8+ T cells, respectively. In this study, we generated GPC3-targeted CAR-T cells overexpressing GLUT1 or AGK for the treatment of HCC. GPC3-targeted CAR-T cells overexpressing GLUT1 or AGK specifically and effectively lysed GPC3-positive tumor cells in vitro in an antigen-dependent manner. Furthermore, GLUT1 or AGK overexpression protected CAR-T cells from apoptosis during repeated exposures to tumor cells. Compared with second-generation CAR-T cells, GPC3-targeted CAR-T cells overexpressing GLUT1 or AGK exhibited greater CD8+ T-cell persistence in vivo and better antitumor effects in HCC allograft mouse models. Finally, we revealed that GLUT1 or AGK maintained anti-apoptosis ability in CD8+ T cells via activation of the PI3K/Akt pathway. This finding might identify a therapeutic strategy for advanced HCC.

Keywords:  GPC3-targeted CAR-T cells; PI3K/Akt pathway; acylglycerol kinase; glucose transporter type 1; hepatocellular carcinoma

DOI:  https://doi.org/10.1038/s41401-024-01287-8
Discov Oncol. 2024 May 15. 15(1): 167

Targeting neutrophil elastase is a promising direction for future cancer treatment.

Wangqiang Jia, Yudong Mao, Qianwen Luo, Jiang Wu, Quanlin Guan.

  Neutrophil elastase (NE) is a proteolytic enzyme released extracellular during the formation of neutrophil extracellular traps (NETs) through degranulation. In addition to participating in the body's inflammatory response, NE also plays an important role in cancer. It can promote tumor proliferation, migration, and invasion, induce epithelial-mesenchymal transition (EMT), and change the tumor microenvironment (TME) to promote tumor progression. Concurrently, NE promotes systemic treatment resistance by inducing EMT. However, it can also selectively kill cancer cells and attenuate tumor development. Sivelestat is a specific NE inhibitor that can be used in the perioperative period of esophageal cancer patients to reduce the incidence of postoperative complications after esophagectomy. In addition, the combination of sivelestat and trastuzumab can enhance the efficacy of human epidermal growth factor receptor 2(HER 2) positive breast cancer patients. Meanwhile, targeting the human antibody domains and fragments of NE is also a new way to treat cancer and inflammation-related diseases. This review provides valuable insights into the role of NE in cancer treatment. Additionally, we discuss the challenges associated with the clinical application of sivelestat. By shedding light on the promising potential of NE, this review contributes to the advancement of cancer treatment strategies.

Keywords:  Cancer; Metastasis; Neutrophil elastase; Proliferation; Sivelestat

DOI:  https://doi.org/10.1007/s12672-024-01010-3
Clin Cancer Res. 2024 May 15.

Arming Vδ2 T cells with chimeric antigen receptors to combat cancer.

Pauline Thomas, Pierre Paris, Claire Pecqueur.

Immunotherapy has emerged as a promising approach in the field of cancer treatment, with chimeric antigen receptor (CAR) T cell therapy demonstrating remarkable success. However, challenges such as tumor antigen heterogeneity, immune evasion, and limited persistence of CAR-T cells have prompted the exploration of alternative cell types for CAR-based strategies. Gamma delta T cells, a unique subset of lymphocytes with inherent tumor recognition capabilities and versatile immune functions, have garnered increasing attention in recent years. In this review, we will present how arming Vδ2-T cells might be the basis for next-generation immunotherapies against solid tumors. Following a comprehensive overview of γδ T cell biology and innovative CAR engineering strategies, we will discuss the clinical potential of Vδ2 CAR-T cells to overcome the current limitations of immunotherapy in solid tumors. Indeed, while applications of Vδ2 CAR-T cells in cancer research are relatively in their infancy and many challenges are yet to be identified, Vδ2 CAR-T cells represent a promising breakthrough in cancer immunotherapy.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-3495
Mol Ther. 2024 May 14. pii: S1525-0016(24)00315-0. [Epub ahead of print]

Granzyme B-activated IL18 potentiates αβ and γδ CAR T-cell immunotherapy in a tumor-dependent manner.

Caroline M Hull, Daniel Larcombe-Young, Roberta Mazza, Molly George, David M Davies, Anna Schurich, John Maher.

Interleukin (IL)18 is a potent pro-inflammatory cytokine that is activated upon caspase 1 cleavage of the latent precursor, pro-IL18. Therapeutic T-cell armoring with IL18 promotes autocrine stimulation and positive modulation of the tumor microenvironment (TME). However, existing strategies are imperfect since they involve constitutive/ poorly regulated activity, or fail to modify the TME. Here, we have substituted the caspase 1 cleavage site within pro-IL18 with that preferred by granzyme B, yielding GzB-IL18. We demonstrate that GzB-IL18 is constitutively released but remains functionally latent unless CAR T-cells are activated, owing to concomitant granzyme B release. Armoring with GzB-IL18 enhances cytolytic activity, proliferation, IFN-γ release and anti-tumor efficacy by a similar magnitude to constitutively active IL18. We also demonstrate that GzB-IL18 provides a highly effective armoring strategy for γδ CAR T-cells, leading to enhanced metabolic fitness and significant potentiation of therapeutic activity. Finally, we show that constitutively active IL18 can unmask CAR T-cell-mediated cytokine release syndrome in immunocompetent mice. By contrast, GzB-IL18 promotes anti-tumor activity and myeloid cell re-programming without inducing such toxicity. Using this stringent system, we have tightly coupled the biological activity of IL18 to the activation state of the host CAR T-cell, favoring safer clinical implementation of this technology.

DOI: https://doi.org/10.1016/j.ymthe.2024.05.013
Thorac Cancer. 2024 May 13.

Enhanced systemic antitumor efficacy of PD-1/PD-L1 blockade with immunological response induced by photodynamic therapy.

Takumi Sonokawa, Yukio Fujiwara, Cheng Pan, Yoshihiro Komohara, Jitsuo Usuda.

   BACKGROUND: Photodynamic therapy (PDT) is an antitumor therapy and has traditionally been regarded as a localized therapy in itself. However, recent reports have shown that it not only exerts a direct cytotoxic effect on cancer cells but also enhances body's tumor immunity. We hypothesized that the immunological response induced by PDT could potentially enhance the efficacy of programmed death-1 (PD-1) / programmed death-ligand 1 (PD-L1) blockade.
METHODS: The cytotoxic effects of PDT on colon 26 cells were investigated in vitro using the WST assay. We investigated whether the antitumor effect of anti-PD-1 antibodies could be amplified by the addition of PDT. We performed combination therapy by randomly allocating tumor-bearing mice to four treatment groups: control, anti-PD-1 antibodies, PDT, and a combination of anti-PD-1 antibodies and PDT. To analyze the tumor microenvironment after treatment, the tumors were resected and pathologically evaluated.
RESULTS: The viability rate of colon 26 cells decreased proportionally with the laser dose. In vivo experiments for combined PDT and anti-PD-1 antibody treatment, combination therapy showed an enhanced antitumor effect compared with the control. Immunohistochemical findings of the tumor microenvironment 10 days after PDT indicated that the number of CD8+ cells, the area of Iba-1+ cells and the area expressing PD-L1 were significantly higher in tumors treated with combination therapy than in tumors treated with anti-PD-1 antibody alone, PDT alone, or the control.
CONCLUSIONS: PDT increased immune cell infiltration into the tumor microenvironment. The immunological response induced by PDT may enhance the efficacy of PD-1/PD-L1 blockade.

Keywords:  anti‐PD‐1; combination therapy; immunological response; photodynamic therapy

DOI:  https://doi.org/10.1111/1759-7714.15325
Sci Transl Med. 2024 May 15. 16(747): eadi2952

Tumor-associated NK cells drive MDSC-mediated tumor immune tolerance through the IL-6/STAT3 axis.

Shi Yong Neo, Le Tong, Joni Chong, Yaxuan Liu, Xu Jing, Mariana M S Oliveira, Yi Chen, Ziqing Chen, Keene Lee, Nutsa Burduli, Xinsong Chen, Juan Gao, Ran Ma, Jia Pei Lim, Jianxin Huo, Shengli Xu, Evren Alici, Stina L Wickström, Felix Haglund, Johan Hartman, Arnika K Wagner, Yihai Cao, Rolf Kiessling, Kong Peng Lam, Lisa S Westerberg, Andreas Lundqvist.

Apart from their killer identity, natural killer (NK) cells have integral roles in shaping the tumor microenvironment. Through immune gene deconvolution, the present study revealed an interplay between NK cells and myeloid-derived suppressor cells (MDSCs) in nonresponders of immune checkpoint therapy. Given that the mechanisms governing the outcome of NK cell-to-myeloid cell interactions remain largely unknown, we sought to investigate the cross-talk between NK cells and suppressive myeloid cells. Upon contact with tumor-experienced NK cells, monocytes and neutrophils displayed increased expression of MDSC-related suppressive factors along with increased capacities to suppress T cells. These changes were accompanied by impaired antigen presentation by monocytes and increased ER stress response by neutrophils. In a cohort of patients with sarcoma and breast cancer, the production of interleukin-6 (IL-6) by tumor-infiltrating NK cells correlated with S100A8/9 and arginase-1 expression by MDSCs. At the same time, NK cell-derived IL-6 was associated with tumors with higher major histocompatibility complex class I expression, which we further validated with b2m-knockout (KO) tumor mice models. Similarly in syngeneic wild-type and IL-6 KO mouse models, we then demonstrated that the accumulation of MDSCs was influenced by the presence of such regulatory NK cells. Inhibition of the IL-6/signal transducer and activator of transcription 3 (STAT3) axis alleviated suppression of T cell responses, resulting in reduced tumor growth and metastatic dissemination. Together, these results characterize a critical NK cell-mediated mechanism that drives the development of MDSCs during tumor immune escape.

DOI: https://doi.org/10.1126/scitranslmed.adi2952
Cureus. 2024 Apr;16(4): e58138

Immune Checkpoint Inhibitors: A Narrative Review on PD-1/PD-L1 Blockade Mechanism, Efficacy, and Safety Profile in Treating Malignancy.

Nicolas D Benelli, Ian Brandon, Karina E Hew.

  Checkpoint inhibitors have been implicated in the treatment of several cancers due to their ability to exploit the immune system's regulatory pathways. This article serves to emphasize the importance of these immunotherapeutic agents and provide further insight into their mechanisms, efficacies, and safety profiles. The main agents in question include programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1). Several literature sources were found to assess the use of these inhibitors in cancers involving the lung, breast, and skin. Several peer-reviewed systematic reviews and the outcomes of clinical trials are combined within this article to support the use and further investigation of these agents in treating neoplasms. Further research into these forms of therapy underscores the revolutionary advancement of oncological interventions, which is important given the rising incidence of neoplasms within populations.

Keywords:  cancer; cancer immunotherapy; immune checkpoint inhibitors; pd-1 inhibitor; pd-l1

DOI:  https://doi.org/10.7759/cureus.58138
CNS Neurosci Ther. 2024 05;30(5): e14729

The biological behavior and clinical outcome of pituitary adenoma are affected by the microenvironment.

Yuhe Li, Xiufang Ren, Wei Gao, Ruikai Cai, Jianqi Wu, Tianqi Liu, Xin Chen, Daoming Jiang, Chong Chen, Quan Cheng, Anhua Wu, Wen Cheng.

   BACKGROUND: Pituitary adenoma is one of the most common brain tumors. Most pituitary adenomas are benign and can be cured by surgery and/or medication. However, some pituitary adenomas show aggressive growth with a fast growth rate and are resistant to conventional treatments such as surgery, drug therapy, and radiation therapy. These tumors, referred to as refractory pituitary adenomas, often relapse or regrow in the early postoperative period. The tumor microenvironment (TME) has recently been identified as an important factor affecting the biological manifestations of tumors and acts as the main battlefield between the tumor and the host immune system.
MAIN BODY: In this review, we focus on describing TME in pituitary adenomas and refractory pituitary adenomas. Research on the immune microenvironment of pituitary adenomas is currently focused on immune cells such as macrophages and lymphocytes, and extensive research and experimental verifications are still required regarding other components of the TME. In particular, studies are needed to determine the role of the TME in the specific biological behaviors of refractory pituitary adenomas, such as high invasion, fast recurrence rate, and high tolerance to traditional treatments and to identify the mechanisms involved.
CONCLUSION: Overall, we summarize the similarities and differences between the TME of pituitary adenomas and refractory pituitary adenomas as well as the changes in the biological behavior of pituitary adenomas that may be caused by the microenvironment. These changes greatly affect the outcome of patients.

Keywords:  biological behavior; outcome; pituitary adenoma; refractory pituitary adenoma; tumor microenvironment

DOI:  https://doi.org/10.1111/cns.14729
Int Immunopharmacol. 2024 May 11. pii: S1567-5769(24)00772-0. [Epub ahead of print]134 112253

Heterogeneity of myeloid cells in common cancers: Single cell insights and targeting strategies.

Zhi-Qian Jing, Zhi-Qi Luo, Si-Rui Chen, Zhi-Jun Sun.

  Tumor microenvironment (TME), is characterized by a complex and heterogenous composition involving a substantial population of immune cells. Myeloid cells comprising over half of the solid tumor mass, are undoubtedly one of the most prominent cell populations associated with tumors. Studies have unambiguously established that myeloid cells play a key role in tumor development, including immune suppression, pro-inflammation, promote tumor metastasis and angiogenesis, for example, tumor-associated macrophages promote tumor progression in a variety of common tumors, including lung cancer, through direct or indirect interactions with the TME. However, due to previous technological constraints, research on myeloid cells often tended to be conducted as studies with low throughput and limited resolution. For example, the conventional categorization of macrophages into M1-like and M2-like subsets based solely on their anti-tumor and pro-tumor roles has disregarded their continuum of states, resulting in an inadequate analysis of the high heterogeneity characterizing myeloid cells. The widespread adoption of single-cell RNA sequencing (scRNA-seq) in tumor immunology has propelled researchers into a new realm of understanding, leading to the establishment of novel subsets and targets. In this review, the origin of myeloid cells in high-incidence cancers, the functions of myeloid cell subsets examined through traditional and single-cell perspectives, as well as specific targeting strategies, are comprehensively outlined. As a result of this endeavor, we will gain a better understanding of myeloid cell heterogeneity, as well as contribute to the development of new therapeutic approaches.

Keywords:  Immunotherapy; Myeloid cells; Myelopoiesis; Single-cell RNA sequencing; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.intimp.2024.112253
Discov Oncol. 2024 May 16. 15(1): 170

Interleukin-12 in multimodal tumor therapies for induction of anti-tumor immunity.

Yulian Xu, Xueli Sun, Yunguang Tong.

  Interleukin-12 (IL-12) can be used as an immunomodulator in cancer immunotherapy. And it has demonstrated enormous potential in inhibiting tumor growth and improving the tumor microenvironment (TME) by several preclinical models. However, some disappointing results have showed in the early clinical trials when IL-12 used as a single agent for systemic cancer therapy. Combination therapy is an effective way to significantly fulfill the great potential of IL-12 as an immunomodulator. Here, we discuss the effects of IL-12 combined with traditional methods (chemotherapy, radiotherapy and surgery), targeted therapy or immunotherapy in the preclinical and clinical studies. Moreover, we summarized the potential mechanism underlying the anti-tumor effect of IL-12 in the combination strategies. And we also discussed the delivery methods and tumor-targeted modification of IL-12 and outlines future prospects for IL-12 as an immunomodulator.

Keywords:  Anti-tumor immunity; Combination therapy; Cytokine; IL-12

DOI:  https://doi.org/10.1007/s12672-024-01011-2
Mol Ther. 2024 May 10. pii: S1525-0016(24)00319-8. [Epub ahead of print]

BCKDK Modification Enhances the Anticancer Efficacy of CAR-T Cells by Reprogramming Branched Chain Amino Acid Metabolism.

Quanjun Yang, Xinting Zhu, Ping Huang, Chunyan Li, Leng Han, Yonglong Han, Run Gan, Bo Xin, Yixing Tu, Shumin Zhou, Ting Yuan, Juan Hao, Chunqiong Li, Li Zhang, Lei Shi, Cheng Guo.

Altered Branched Chain Amino Acids (BCAA), including leucine, isoleucine and valine, are frequently observed in patients with advanced cancer. We evaluated the efficacy of Chimeric Antigen Receptor (CAR) T cell-mediated cancer cell lysis potential in the immune microenvironment of BCAA supplementation and deletion. BCAA supplementation increased cancer cell killing percentage, while accelerating BCAA catabolism and deceasing BCAA transporter decreased cancer cell lysis efficacy. We thus designed BCKDK engineering CAR T cells for the reprogramming of BCAA metabolism in the tumor microenvironment based on the genotype and phenotype modification. BCKDK overexpression (OE) in CAR-T cells significantly improved cancer cell lysis, while BCKDK knockout (KO) resulted in inferior lysis potential. In an in vivo experiment, BCKDK-OE CAR-T cells treatment significantly prolonged the survival of mice bearing NALM6-GL cancer cells, with the differentiation of central memory cells and the increasing proportion of CAR-T cells in peripheral circulation. BCKDK-KO CAR-T cells treatment resulted in shorter survival and decreasing percentage of CAR-T cells in peripheral circulation. In conclusion, BCKDK engineered CAR-T cells exert distinct phenotype for the superior anticancer efficiency.

DOI: https://doi.org/10.1016/j.ymthe.2024.05.017
Cell Mol Biol Lett. 2024 May 14. 29(1): 73

The role of proinflammatory cytokines and CXC chemokines (CXCL1-CXCL16) in the progression of prostate cancer: insights on their therapeutic management.

Amin Ullah, Wang Jiao, Bairong Shen.

  Reproductive cancers are malignancies that develop in the reproductive organs. One of the leading cancers affecting the male reproductive system on a global scale is prostate cancer (PCa). The negative consequences of PCa metastases endure and are severe, significantly affecting mortality and life quality for those who are affected. The association between inflammation and PCa has captured interest for a while. Inflammatory cells, cytokines, CXC chemokines, signaling pathways, and other elements make up the tumor microenvironment (TME), which is characterized by inflammation. Inflammatory cytokines and CXC chemokines are especially crucial for PCa development and prognosis. Cytokines (interleukins) and CXC chemokines such as IL-1, IL-6, IL-7, IL-17, TGF-β, TNF-α, CXCL1-CXCL6, and CXCL8-CXCL16 are thought to be responsible for the pleiotropic effects of PCa, which include inflammation, progression, angiogenesis, leukocyte infiltration in advanced PCa, and therapeutic resistance. The inflammatory cytokine and CXC chemokines systems are also promising candidates for PCa suppression and immunotherapy. Therefore, the purpose of this work is to provide insight on how the spectra of inflammatory cytokines and CXC chemokines evolve as PCa develops and spreads. We also discussed recent developments in our awareness of the diverse molecular signaling pathways of these circulating cytokines and CXC chemokines, as well as their associated receptors, which may one day serve as PCa-targeted therapies. Moreover, the current status and potential of theranostic PCa therapies based on cytokines, CXC chemokines, and CXC receptors (CXCRs) are examined.

Keywords:  CXC chemokines; Cytokines; Inflammation; Prostate cancer (PCa); Targeted therapies

DOI:  https://doi.org/10.1186/s11658-024-00591-9
Cancers (Basel). 2024 Apr 23. pii: 1626. [Epub ahead of print]16(9):

Predictive and Prognostic Relevance of Tumor-Infiltrating Immune Cells: Tailoring Personalized Treatments against Different Cancer Types.

Tikam Chand Dakal, Nancy George, Caiming Xu, Prashanth Suravajhala, Abhishek Kumar.

  TIICs are critical components of the TME and are used to estimate prognostic and treatment responses in many malignancies. TIICs in the tumor microenvironment are assessed and quantified by categorizing immune cells into three subtypes: CD66b+ tumor-associated neutrophils (TANs), FoxP3+ regulatory T cells (Tregs), and CD163+ tumor-associated macrophages (TAMs). In addition, many cancers have tumor-infiltrating M1 and M2 macrophages, neutrophils (Neu), CD4+ T cells (T-helper), CD8+ T cells (T-cytotoxic), eosinophils, and mast cells. A variety of clinical treatments have linked tumor immune cell infiltration (ICI) to immunotherapy receptivity and prognosis. To improve the therapeutic effectiveness of immune-modulating drugs in a wider cancer patient population, immune cells and their interactions in the TME must be better understood. This study examines the clinicopathological effects of TIICs in overcoming tumor-mediated immunosuppression to boost antitumor immune responses and improve cancer prognosis. We successfully analyzed the predictive and prognostic usefulness of TIICs alongside TMB and ICI scores to identify cancer's varied immune landscapes. Traditionally, immune cell infiltration was quantified using flow cytometry, immunohistochemistry, gene set enrichment analysis (GSEA), CIBERSORT, ESTIMATE, and other platforms that use integrated immune gene sets from previously published studies. We have also thoroughly examined traditional limitations and newly created unsupervised clustering and deconvolution techniques (SpatialVizScore and ProTICS). These methods predict patient outcomes and treatment responses better. These models may also identify individuals who may benefit more from adjuvant or neoadjuvant treatment. Overall, we think that the significant contribution of TIICs in cancer will greatly benefit postoperative follow-up, therapy, interventions, and informed choices on customized cancer medicines.

Keywords:  cancers; immunotherapy; personalized treatment; precision medicine; predictive biomarkers; prognostic biomarkers; tumor microenvironment (TME); tumor-infiltrating immune cells (TIICs)

DOI:  https://doi.org/10.3390/cancers16091626
Biochim Biophys Acta Mol Basis Dis. 2024 May 11. pii: S0925-4439(24)00225-4. [Epub ahead of print]1870(6): 167236

PAK1 inhibition increases TRIM21-induced PD-L1 degradation and enhances responses to anti-PD-1 therapy in pancreatic cancer.

Kai Wang, Lili Yan, Xun Qiu, Huan Chen, Fengqiang Gao, Wenwen Ge, Zhengxing Lian, Xuyong Wei, Shuai Wang, Hong He, Xiao Xu.

  Pancreatic ductal adenocarcinoma (PDA) is a common malignancy with a 5-year survival <10 %. Immunosuppressive tumor microenvironment (TME) plays a critical role in the progression of PDA. In recent years, programmed death-ligand 1 (PD-L1)/programmed cell death protein-1 (PD-1) blockade has emerged as a potent anti-tumor immunotherapy, while is yet to achieve significant clinical benefits for PDA patients. P21-Activated kinase 1 (PAK1) is highly upregulated in PDA and has been reported to be involved in the regulation of anti-tumor immunity. This study aims to investigate the combined effect of PAK1 inhibition and anti-PD-1 therapy on PDA and the underlying mechanisms. We have shown that PAK1 expression positively correlated with PD-L1 in PDA patients, and that inhibition of PAK1 downregulated PD-L1 expression of PDA cells. More importantly, we have demonstrated that PAK1 competed with PD-L1 in binding to tripartite motif-containing protein 21 (TRIM21), a ubiquitin E3 ligase, resulting in less ubiquitination and degradation of PD-L1. Moreover, PAK1 inhibition promoted CD8+ T cells activation and infiltration. In a murine PDA model, the combination of PAK1 inhibition and anti-PD-1 therapy showed significant anti-tumor effects compared with the control or monotherapy. Our results indicated that the combination of PAK1 inhibition and anti-PD-1 therapy would be a more effective treatment for PDA patients.

Keywords:  P21-activated kinase 1; Pancreatic cancer; Programmed cell death protein-1; Programmed death-ligand 1; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbadis.2024.167236
Purinergic Signal. 2024 May 16.

Metastasis and angiogenesis in cervical cancer: key aspects of purinergic signaling in platelets and possible therapeutic targets.

Paula C L Faria, Rackel S Resende, Andréia M Cardoso.

  Cervical cancer ranks as the fourth most common and fatal cancer among women worldwide. Studies have demonstrated a strong association between purinergic platelet signaling and tumor progression in this type of cancer. The literature shows that neoplastic cells, when in the bloodstream, secrete adenosine triphosphate (ATP) and adenosine nucleotide diphosphate (ADP) that act on their corresponding platelet P2Y and P2X receptors. The interaction of these nucleotides with their receptors results in platelet activation and degranulation, ensuing several consequences, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor, matrix metalloproteinases, ADP, and ATP. These molecules play essential roles in angiogenesis and tumor metastasis in cervical cancer. Several purinergic receptors are found in endothelial cells. Their activation, especially P2Y2, by the nucleotides released by platelets can induce relaxation of the endothelial barrier and consequent extravasation of tumor cells, promoting the development of metastases. Cancer cells that enter the bloodstream during the metastatic process are also subject to high shear stress and immune surveillance. In this context, activated platelets bind to circulating tumor cells and protect them against shear stress and the host's immune system, especially against natural killer cells, facilitating their spread throughout the body. Furthermore, activation of the P2Y12 receptor present on the platelet surface promotes the release of VEGF, the main inducer of angiogenesis in cervical cancer, in addition to increasing the concentration of several other pro-angiogenic molecules. Therefore, this review will address the role of platelet purinergic signaling in tumor progression of cervical cancer and propose possible therapeutic targets.

Keywords:  Angiogenesis; Cervical cancer; Metastasis; Platelets; Purinergic system; Therapeutic targets

DOI:  https://doi.org/10.1007/s11302-024-10020-3
Cancer Immunol Res. 2024 May 13.

IL-3-driven T cell-basophil crosstalk enhances antitumor immunity.

Jian Wei, Colleen L Mayberry, Xiaoting Lv, Fangyan Hu, Taushif Khan, Natalie A Logan, John J Wilson, John D Sears, Damien Chaussabel, Chih-Hao Chang.

Cytotoxic T lymphocytes (CTLs) are pivotal in combating cancer, yet their efficacy is often hindered by the immunosuppressive tumor microenvironment, resulting in exhaustion. This study investigates the role of interleukin (IL)-3 in orchestrating anti-tumor immunity through CTL modulation. Intratumoral CTLs undergo a progressive decline in IL-3 production, which is correlated with impaired cytotoxic function. Augmenting IL-3 supplementation, through intraperitoneal administration of recombinant IL-3, IL-3-expressing tumor cells, or IL-3-engineered CD8+ T cells, confers protection against tumor progression, concomitant with increased CTL activity. CTLs are critical in this therapeutic efficacy as IL-3 demonstrates no impact on tumor growth in Rag1 knockout mice or following CD8+ T cell-depletion. Rather than acting directly, CTL-derived IL-3 exerts its influence on basophils, synergistically amplifying anti-tumor immunity within CTLs. Introducing IL-3-activated basophils retards tumor progression, whereas basophil depletion diminishes the effectiveness of IL-3 supplementation. Furthermore, IL-3 prompts basophils to produce IL-4, which subsequently elevates CTL IFN-γ production and viability. Notably, the importance of basophil-derived IL-4 is evident from the absence of benefits of IL-3-supplementatation in IL-4 knockout tumor-bearing mice. Overall, this research unveils IL-3-mediated CTL-basophil crosstalk in regulating anti-tumor immunity, and offers the prospect of harnessing IL-3 sustenance as a promising approach for optimizing and enhancing cancer immunotherapy.

DOI: https://doi.org/10.1158/2326-6066.CIR-23-0851
Medicine (Baltimore). 2024 May 17. 103(20): e38078

The role of the microscopic world: Exploring the role and potential of intratumoral microbiota in cancer immunotherapy.

Liqiang Zhang, Liang Yu.

Microorganisms, including bacteria, viruses, and fungi, coexist in the human body, forming a symbiotic microbiota that plays a vital role in human health and disease. Intratumoral microbial components have been discovered in various tumor tissues and are closely linked to the occurrence, progression, and treatment results of cancer. The intratumoral microbiota can enhance antitumor immunity through mechanisms such as activating the stimulator of interferon genes signaling pathway, stimulating T and NK cells, promoting the formation of TLS, and facilitating antigen presentation. Conversely, the intratumoral microbiota might suppress antitumor immune responses by increasing reactive oxygen species levels, creating an anti-inflammatory environment, inducing T cell inactivation, and enhancing immune suppression, thereby promoting cancer progression. The impact of intratumoral microbiota on antitumor immunity varies based on microbial composition, interactions with cancer cells, and the cancer's current state. A deep understanding of the complex interactions between intratumoral microbiota and antitumor immunity holds the potential to bring new therapeutic strategies and targets to cancer immunotherapy.

DOI: https://doi.org/10.1097/MD.0000000000038078