bims-mecami 2024-07-14 papers

Issue of 2024–07–14
six papers selected by
Oltea Sampetrean, Keio University

Theranostics. 2024 ;14(10): 3793-3809

CBX4 suppresses CD8+ T cell antitumor immunity by reprogramming glycolytic metabolism.

Jingzeng Wang, Wenlong Jia, Xi Zhou, Zhibo Ma, Jing Liu, Peixiang Lan.

Rationale: CD8+ T cells undergo a series of metabolic reprogramming processes during their activation and proliferation, including increased glycolysis, decreased aerobic oxidation of sugars, increased amino acid metabolism and increased protein synthesis. However, it is still unclear what factors regulate these metabolic reprogramming processes in CD8+ T cells in the tumor immune microenvironment. Methods: T cell chromobox protein 4 (CBX4) knock-out mice models were used to determine the role of CBX4 in CD8+ T cells on the tumor immune microenvironment and tumor progression. Flow cytometry, Cut-Tag qPCR, Chip-seq, immunoprecipitation, metabolite detection, lentivirus infection and adoptive T cells transfer were performed to explore the underlying mechanisms of CBX4 knock-out in promoting CD8+ T cell activation and inhibiting tumor growth. Results: We found that CBX4 expression was induced in tumor-infiltrating CD8+ T cells and inhibited CD8+ T cell function by regulating glucose metabolism in tumor tissue. Mechanistically, CBX4 increases the expression of the metabolism-associated molecule aldolase B (Aldob) through sumoylation of trans-acting transcription factor 1 (SP1) and Krüppel-like factor 3 (KLF3). In addition, Aldob inhibits glycolysis and ATP synthesis in T cells by reducing the phosphorylation of the serine/threonine protein kinase (Akt) and ultimately suppresses CD8+ T cell function. Significantly, knocking out CBX4 may improve the efficacy of anti-PD-1 therapy by enhancing the function of CD8+ T cells in the tumor microenvironment. Conclusion: CBX4 is involved in CD8+ T cell metabolic reprogramming and functional persistence in tumor tissues, and serves as an inhibitor in CD8+ T cells' glycolysis and effector function.

Keywords: Aldob; CBX4; CD8+ T cell; anti-tumor; glucose metabolism

DOI: https://doi.org/10.7150/thno.95748

Gut. 2024 Jul 09. pii: gutjnl-2024-332429. [Epub ahead of print]

Glutamine metabolic competition drives immunosuppressive reprogramming of intratumour GPR109A+ myeloid cells to promote liver cancer progression.

Yang Yang, Tianduo Pei, Chaobao Liu, Mingtao Cao, Xiaolin Hu, Jie Yuan, Fengqian Chen, Bao Guo, Yuemei Hong, Jibin Liu, Bin Li, Xiaoguang Li, Hui Wang.

OBJECTIVE: The metabolic characteristics of liver cancer drive considerable hurdles to immune cells function and cancer immunotherapy. However, how metabolic reprograming in the tumour microenvironment impairs the antitumour immune response remains unclear.
DESIGN: Human samples and multiple murine models were employed to evaluate the correlation between GPR109A and liver cancer progression. GPR109A knockout mice, immune cells depletion and primary cell coculture models were used to determine the regulation of GPR109A on tumour microenvironment and identify the underlying mechanism responsible for the formation of intratumour GPR109A+myeloid cells.
RESULTS: We demonstrate that glutamine shortage in liver cancer tumour microenvironment drives an immunosuppressive GPR109A+myeloid cells infiltration, leading to the evasion of immune surveillance. Blockade of GPR109A decreases G-MDSCs and M2-like TAMs abundance to trigger the antitumour responses of CD8+ T cells and further improves the immunotherapy efficacy against liver cancer. Mechanistically, tumour cells and tumour-infiltrated myeloid cells compete for glutamine uptake via the transporter SLC1A5 to control antitumour immunity, which disrupts the endoplasmic reticulum (ER) homoeostasis and induces unfolded protein response of myeloid cells to promote GPR109A expression through IRE1α/XBP1 pathway. The restriction of glutamine uptake in liver cancer cells, as well as the blockade of IRE1α/XBP1 signalling or glutamine supplementation, can eliminate the immunosuppressive effects of GPR109A+ myeloid cells and slow down tumour progression.
CONCLUSION: Our findings identify the immunometabolic crosstalk between liver cancer cells and myeloid cells facilitates tumour progression via a glutamine metabolism/ER stress/GPR109A axis, suggesting that GPR109A can be exploited as an immunometabolic checkpoint and putative target for cancer treatment.

Keywords: HEPATOCELLULAR CARCINOMA; IMMUNOLOGY IN HEPATOLOGY; IMMUNOTHERAPY

DOI: https://doi.org/10.1136/gutjnl-2024-332429

J Immunother Cancer. 2024 Jul 08. pii: e008811. [Epub ahead of print]12(7):

Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma.

Yang Chen, Yu Zhou, Ran Ren, Yu Chen, Juan Lei, Yongsheng Li.

BACKGROUND: While anti-programmed cell death protein-1 (PD-1) monotherapy has shown effectiveness in treating lung cancer, its response rate is limited to approximately 20%. Recent research suggests that abnormal lipid metabolism in patients with lung adenocarcinoma may hinder the efficacy of anti-PD-1 monotherapy.
METHODS: Here, we delved into the patterns of lipid metabolism in patients with The Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD) and their correlation with the immune microenvironment's cellular infiltration characteristics of the tumor. Furthermore, the lipid metabolism score (LMS) system was constructed, and based on the LMS system, we further performed screening for potential agents targeting lipid metabolism. The mechanism of MK1775 was further validated using RNA sequencing, co-culture technology, and in vivo experiments.
RESULTS: We developed an LSM system and identified a potential sensitizing agent, MK1775, which targets lipid metabolism and enhances the effects of anti-PD-1 treatment. Our results demonstrate that MK1775 inhibits tumor progression by influencing lipid crosstalk between tumor cells and tumor-associated macrophages and CD8+T cells, thereby increasing the effectiveness of anti-PD-1 treatment. Further, we found that MK1775 inhibited the phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway, which on one hand downregulated FASN-mediated synthesis of fatty acids (FAs) to inhibit fatty acid oxidation of tumor-associated macrophages, and on the other hand, promoted IRF-mediated secretion of CXCL10 and CXCL11 to facilitate the infiltration of CD8+ T cells.
CONCLUSIONS: These findings emphasize the important role of lipid metabolism in shaping the complex tumor microenvironment. By manipulating the intricate intricacies of lipid metabolism within the tumor microenvironment, we can uncover and develop promising strategies to sensitize immunotherapy, potentially revolutionizing cancer treatment approaches.

Keywords: Immune Checkpoint Inhibitor; Lung Cancer; Macrophage; Tumor microenvironment - TME

DOI: https://doi.org/10.1136/jitc-2024-008811

Cancer Commun (Lond). 2024 Jul 12.

Cellular senescence and metabolic reprogramming: Unraveling the intricate crosstalk in the immunosuppressive tumor microenvironment.

Fusheng Zhang, Junchen Guo, Shengmiao Yu, Youwei Zheng, Meiqi Duan, Liang Zhao, Yihan Wang, Zhi Yang, Xiaofeng Jiang.

The intrinsic oncogenic mechanisms and properties of the tumor microenvironment (TME) have been extensively investigated. Primary features of the TME include metabolic reprogramming, hypoxia, chronic inflammation, and tumor immunosuppression. Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME. Specifically, hypoxic adaptation, metabolic dysregulation, and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation, thereby promoting the progression of tumor events. This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME, with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells. The available findings suggest that components of the TME collectively contribute to the progression of tumor events. The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.

Keywords: cellular senescence; chronic inflammation; hypoxia; immunosuppressive tumor microenvironment; metabolic reprogramming; tumor‐targeted therapy

DOI: https://doi.org/10.1002/cac2.12591

Cell Host Microbe. 2024 Jul 10. pii: S1931-3128(24)00192-6. [Epub ahead of print]32(7): 1045-1047

Microbiota alert: Proteobacteria consume arginine to dampen omental antitumor immunity.

Xian Du, Zuliang Jie, Qiang Zou.

The microbiota can impact antitumor immunity, but whether the microbiota regulates omental antitumor immunity remains elusive. In this issue of Cell Host & Microbe, Meza-Perez et al. demonstrated that Proteobacteria consume arginine to increase Treg cell suppressive capacity and inhibit antitumor immune responses, promoting tumor growth in the omentum.

DOI: https://doi.org/10.1016/j.chom.2024.05.020

J Gastrointest Oncol. 2024 Jun 30. 15(3): 1282-1296

Lactic acid: a narrative review of a promoter of the liver cancer microenvironment.

Junhe Chen, Guifang He, Duo Cai, Elisa Giovannetti, Kentaro Inamura, Shihai Liu, Wenzhe Ma.

Background and Objective: Lactic acid is a metabolite of glycolysis produced in the body, and its production is thought to be a mechanism by which cancer cells evade immune surveillance. Immune evasion and metabolic changes are well established as basic hallmarks of cancer. Although lactate has long been considered a waste product, it is now generally recognized to be a versatile small-molecule chemical that plays an important part in the tumor microenvironment (TME), with increased lactate production linked to the development of human malignancies. Metabolism in liver cancer is redirected toward glycolysis, which enhances the production of metabolic compounds used by tumor cells to produce proteins, lipids, and nucleotides, enabling them to maintain high proliferation rates and to establish the TME. Dysregulation of metabolic activity in liver cancer may impair antitumor responses owing to the immunosuppressive activity of the lactate produced by anaerobic glycolytic rates in tumor cells. This review primarily explores the link connection between lactic acid and the TME; evaluates the role of lactic acid in the occurrence, metastasis, prognosis, and treatment of liver cancer. Additionally, it investigates the associated pathways as potential targets for liver cancer treatment.
Methods: Literature searches were conducted in PubMed, Web of Science, and Google Scholar, with the publication date of the most recent article included being January 2024. After eliminating duplicate articles and less relevant articles through titles and abstracts, we selected 113 articles for this review. We categorized references into two categories. One is to classify the content into lactate-related, liver cancer-related and tumor metabolism-related. The other is to classify the article types, which are divided into reviews, research articles and clinical trials. Additionally, we consulted the reference lists of the relevant articles to ensure coverage was comprehensive and unbiased.
Key Content and Findings: The connection between lactic acid and the TME has recently become an area of intense research interest, and many related articles have been published in this field. The main finding of this review is to summarize the proven link between lactate and the TME and its possible impact on the TME of liver cancer. And analyzed the potential of lactate in liver cancer treatment and prognosis prediction.
Conclusions: Lactate may be key to developing novel approaches in the future treatment of liver cancer. Related research on the combination of classic therapies and molecular targeted drugs may provide innovative medicines that more selectively regulate immune cell activity.

Keywords: Lactic acid; cancer metabolism; immune cells; liver cancer; tumor microenvironment (TME)

DOI: https://doi.org/10.21037/jgo-24-368