bims-mecami 2024-12-01 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2024–12–01
ten papers selected by
Oltea Sampetrean, Keio University

Metabolic Reprogramming of Immune Cells in the Tumor Microenvironment.
Emerging role of metabolic reprogramming in the immune microenvironment and immunotherapy of thyroid cancer.
Q&A with Ping Gao.
Why and how citrate may sensitize malignant tumors to immunotherapy.
Q&A with Ilaria Elia.
Dietary Restriction Enhances CD8⁺ T Cell Ketolysis to Limit Exhaustion and Boost Anti-Tumor Immunity.
ACSS1-dependent acetate utilization rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis.
Circadian immunometabolism: A future insight for targeted therapy in cancer.
The interplay of EBV virus and cell metabolism in lung cancer.
Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy.

Int J Mol Sci. 2024 Nov 14. pii: 12223. [Epub ahead of print]25(22):

Metabolic Reprogramming of Immune Cells in the Tumor Microenvironment.

Jing Wang, Yuanli He, Feiming Hu, Chenchen Hu, Yuanjie Sun, Kun Yang, Shuya Yang.

  Metabolic reprogramming of immune cells within the tumor microenvironment (TME) plays a pivotal role in shaping tumor progression and responses to therapy. The intricate interplay between tumor cells and immune cells within this ecosystem influences their metabolic landscapes, thereby modulating the immune evasion tactics employed by tumors and the efficacy of immunotherapeutic interventions. This review delves into the metabolic reprogramming that occurs in tumor cells and a spectrum of immune cells, including T cells, macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSCs), within the TME. The metabolic shifts in these cell types span alterations in glucose, lipid, and amino acid metabolism. Such metabolic reconfigurations can profoundly influence immune cell function and the mechanisms by which tumors evade immune surveillance. Gaining a comprehensive understanding of the metabolic reprogramming of immune cells in the TME is essential for devising novel cancer therapeutic strategies. By targeting the metabolic states of immune cells, it is possible to augment their anti-tumor activities, presenting new opportunities for immunotherapeutic approaches. These strategies hold promise for enhancing treatment outcomes and circumventing the emergence of drug resistance.

Keywords:  immune cells; immunotherapy; metabolic reprogramming; the tumor microenvironment

DOI:  https://doi.org/10.3390/ijms252212223
Int Immunopharmacol. 2024 Nov 26. pii: S1567-5769(24)02224-0. [Epub ahead of print]144 113702

Emerging role of metabolic reprogramming in the immune microenvironment and immunotherapy of thyroid cancer.

Shouhua Li, Hengtong Han, Kaili Yang, Xiaoxiao Li, Libin Ma, Ze Yang, Yong-Xun Zhao.

  The metabolic reprogramming of cancer cells is a hallmark of many malignancies. To meet the energy acquisition needs of tumor cells for rapid proliferation, tumor cells reprogram their nutrient metabolism, which is caused by the abnormal expression of transcription factors and signaling molecules related to energy metabolic pathways as well as the upregulation and downregulation of abnormal metabolic enzymes, receptors, and mediators. Thyroid cancer (TC) is the most common endocrine tumor, and immunotherapy has become the mainstream choice for clinical benefit after the failure of surgical, endocrine, and radioiodine therapies. TC change the tumor microenvironment (TME) through nutrient competition and metabolites, causing metabolic reprogramming of immune cells, profoundly changing immune cell function, and promoting immune evasion of tumor cells. A deeper understanding of how metabolic reprogramming alters the TME and controls immune cell fate and function will help improve the effectiveness of TC immunotherapy and patient outcomes. This paper aims to elucidate the metabolic communication that occurs between immune cells around TC and discusses how metabolic reprogramming in TC affects the immune microenvironment and the effectiveness of anti-cancer immunotherapy. Finally, targeting key metabolic checkpoints during metabolic reprogramming, combined with immunotherapy, is a promising strategy.

Keywords:  Immune microenvironment; Immunometabolism; Immunotherapy; Metabolic reprogramming; Thyroid cancers

DOI:  https://doi.org/10.1016/j.intimp.2024.113702
Cell Rep. 2024 Nov 26. pii: S2211-1247(24)01351-2. [Epub ahead of print]43(11): 115000

Q&A with Ping Gao.

Ping Gao.

  Ping Gao, guest editor of the cancer metabolism special issue, spoke with Cell Reports about his scientific interests and his lab's focus on investigating the metabolic reprogramming in cancer cells and immune cells in the tumor microenvironment. Ping also discussed recent developments and future directions in the field.

Keywords:  CP: Cancer; CP: Metabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.115000
Drug Resist Updat. 2024 Nov 26. pii: S1368-7646(24)00135-3. [Epub ahead of print]78 101177

Why and how citrate may sensitize malignant tumors to immunotherapy.

Philippe Icard, Mathilde Prieto, Antoine Coquerel, Ludovic Fournel, Joseph Gligorov, Johanna Noel, Adrien Mouren, Anthony Dohan, Marco Alifano, Luca Simula.

  Immunotherapy, either alone or in combination with chemotherapy, has demonstrated limited efficacy in a variety of solid cancers. Several factors contribute to explaining primary or secondary resistance. Among them, cancer cells, whose metabolism frequently relies on aerobic glycolysis, promote exhaustion of cytotoxic immune cells by diverting the glucose in the tumor microenvironment (TME) to their own profit, while secreting lactic acid that sustains the oxidative metabolism of immunosuppressive cells. Here, we propose to combine current treatment based on the use of immune checkpoint inhibitors (ICIs) with high doses of sodium citrate (SCT) because citrate inhibits cancer cell metabolism (by targeting both glycolysis and oxidative metabolism) and may active anti-tumor immune response. Indeed, as showed in preclinical studies, SCT reduces cancer cell growth, promoting cell death and chemotherapy effectiveness. Furthermore, since the plasma membrane citrate carrier pmCIC is mainly expressed in cancer cells and low or not expressed in immune and non-transformed cells, we argue that the inhibition of cancer cell metabolism by SCT may increase glucose availability in the TME, thus promoting functionality of anti-tumor immune cells. Concomitantly, the decrease in the amount of lactic acid in the TME may reduce the functionality of immunosuppressive cells. Preclinical studies have shown that SCT can enhance the anti-tumor immune response through an enhancement of T cell infiltration and activation, and a repolarization of macrophages towards a TAM1-like phenotype. Therefore, this simple and cheap strategy may have a major impact to increase the efficacy of current immunotherapies in human solid tumors and we encourage testing it in clinical trials.

Keywords:  ICI; cancer; citrate; immunotherapy; lactate; metabolism

DOI:  https://doi.org/10.1016/j.drup.2024.101177
Cell Rep. 2024 Nov 26. pii: S2211-1247(24)01350-0. [Epub ahead of print]43(11): 114999

Q&A with Ilaria Elia.

Ilaria Elia.

  Ilaria Elia, guest editor of the cancer metabolism special issue, spoke with Cell Reports about her scientific interests and her lab's focus on investigating the metabolic interactions between cancer cells and immune cells within the tumor microenvironment. Ilaria also discussed recent developments and future directions in the field.

Keywords:  CP: Cancer; CP: Metabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.114999
bioRxiv. 2024 Nov 15. pii: 2024.11.14.621733. [Epub ahead of print]

Dietary Restriction Enhances CD8⁺ T Cell Ketolysis to Limit Exhaustion and Boost Anti-Tumor Immunity.

Brandon M Oswald, Lisa M DeCamp, Joseph Longo, Michael S Dahabieh, Nicholas Bunda, Shixin Ma, McLane J Watson, Ryan D Sheldon, Michael P Vincent, Benjamin K Johnson, Abigail E Ellis, Molly T Soper-Hopper, Christine N Isaguirre, Hui Shen, Kelsey S Williams, Peter A Crawford, Susan Kaech, H Josh Jang, Connie M Krawczyk, Russell G Jones.

Reducing calorie intake without malnutrition limits tumor progression but the underlying mechanisms are poorly understood. Here we show that dietary restriction (DR) suppresses tumor growth by enhancing CD8 + T cell-mediated anti-tumor immunity. DR reshapes CD8 + T cell differentiation within the tumor microenvironment (TME), promoting the development of effector T cell subsets while limiting the accumulation of exhausted T (Tex) cells, and synergizes with anti-PD1 immunotherapy to restrict tumor growth. Mechanistically, DR enhances CD8 + T cell metabolic fitness through increased ketone body oxidation (ketolysis), which boosts mitochondrial membrane potential and fuels tricarboxylic acid (TCA) cycle-dependent pathways essential for T cell function. T cells deficient for ketolysis exhibit reduced mitochondrial function, increased exhaustion, and fail to control tumor growth under DR conditions. Our findings reveal a critical role for the immune system in mediating the anti-tumor effects of DR, highlighting nutritional modulation of CD8 + T cell fate in the TME as a critical determinant of anti-tumor immunity.

DOI: https://doi.org/10.1101/2024.11.14.621733
Cell Rep. 2024 Nov 21. pii: S2211-1247(24)01339-1. [Epub ahead of print]43(12): 114988

ACSS1-dependent acetate utilization rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis.

Sabina I Hlavaty, Kelsey N Salcido, Katherine A Pniewski, Dzmitry Mukha, Weili Ma, Toshitha Kannan, Joel Cassel, Yellamelli V V Srikanth, Qin Liu, Andrew Kossenkov, Joseph M Salvino, Qing Chen, Zachary T Schug.

  Cancer cells often use alternative nutrient sources to support their metabolism and proliferation. One important alternative nutrient source for many cancers is acetate. Acetate is metabolized into acetyl-coenzyme A (CoA) by acetyl-CoA synthetases 1 and 2 (ACSS1 and ACSS2), which are found in the mitochondria and cytosol, respectively. We show that ACSS1 and ACSS2 are differentially expressed in cancer. Melanoma, breast cancer, and acute myeloid leukemia cells expressing ACSS1 readily use acetate for acetyl-CoA biosynthesis and to fuel mitochondrial metabolism. ACSS1-dependent acetate metabolism decreases the relative contributions of glucose and glutamine to the tricarboxylic acid (TCA) cycle and alters the pentose phosphate pathway and redox state of cancer cells. ACSS1 knockdown decreases acute myeloid leukemia burden in vivo and inhibits melanoma tumor and metastatic growth. Our study highlights a key role for ACSS1-dependent acetate metabolism for cancer growth, raising the potential for ACSS1-targeting therapies in cancer.

Keywords:  ACSS1; ACSS2; ACSS2 inhibitor; AML; CP: Cancer; CP: Metabolism; acetate; cancer; melanoma; metabolism; metastasis

DOI:  https://doi.org/10.1016/j.celrep.2024.114988
Sleep Med Rev. 2024 Nov 19. pii: S1087-0792(24)00135-7. [Epub ahead of print]80 102031

Circadian immunometabolism: A future insight for targeted therapy in cancer.

Manendra Singh Tomar, Mohit, Ashok Kumar, Ashutosh Shrivastava.

  Circadian rhythms send messages to regulate the sleep-wake cycle in living beings, which, regulate various biological activities. It is well known that altered sleep-wake cycles affect host metabolism and significantly deregulate the host immunity. The dysregulation of circadian-related genes is critical for various malignancies. One of the hallmarks of cancer is altered metabolism, the effects of which spill into surrounding microenvironments. Here, we review the emerging literature linking the circadian immunometabolic axis to cancer. Small metabolites are the products of various metabolic pathways, that are usually perturbed in cancer. Genes that regulate circadian rhythms also regulate host metabolism and control metabolite content in the tumor microenvironment. Immune cell infiltration into the tumor site is critical to perform anticancer functions, and altered metabolite content affects their trafficking to the tumor site. A compromised immune response in the tumor microenvironment aids cancer cell proliferation and immune evasion, resulting in metastases. The role of circadian rhythms in these processes is largely overlooked and demands renewed attention in the search for targets against cancer growth and spread. The precision medicine approach requires targeting the circadian immune metabolism in cancer.

Keywords:  Cancer; Circadian rhythms; Clock genes; Immune cells; Immunometabolism; Metabolism

DOI:  https://doi.org/10.1016/j.smrv.2024.102031
J Cell Mol Med. 2024 Nov;28(22): e70088

The interplay of EBV virus and cell metabolism in lung cancer.

Hongwei Wang.

  Epstein-Barr virus infection has been implicated in various cancers, including lung cancer, where it influences cellular metabolism to promote tumorigenesis. This review examines the complex interplay between Epstein-Barr virus and cell metabolism in lung cancer, highlighting viral mechanisms of metabolic reprogramming and their implications for therapeutic strategies. Key viral proteins such as LMP1 and LMP2A manipulate glycolysis, glutaminolysis and lipid metabolism to support viral replication and immune evasion within the tumour microenvironment. Understanding these interactions provides insights into novel therapeutic approaches targeting viral-induced metabolic vulnerabilities in Epstein-Barr virus-associated lung cancer.

Keywords:  Epstein–Barr virus; cell metabolism; glycolysis; immune evasion; lung cancer

DOI:  https://doi.org/10.1111/jcmm.70088
Cells. 2024 Nov 20. pii: 1924. [Epub ahead of print]13(22):

Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy.

Md Ataur Rahman, Mahesh Kumar Yadab, Meser M Ali.

  Identifying definitive biomarkers that predict clinical response and resistance to immunotherapy remains a critical challenge. One emerging factor is extracellular acidosis in the tumor microenvironment (TME), which significantly impairs immune cell function and contributes to immunotherapy failure. However, acidic conditions in the TME disrupt the interaction between cancer and immune cells, driving tumor-infiltrating T cells and NK cells into an inactivated, anergic state. Simultaneously, acidosis promotes the recruitment and activation of immunosuppressive cells, such as myeloid-derived suppressor cells and regulatory T cells (Tregs). Notably, tumor acidity enhances exosome release from Tregs, further amplifying immunosuppression. Tumor acidity thus acts as a "protective shield," neutralizing anti-tumor immune responses and transforming immune cells into pro-tumor allies. Therefore, targeting lactate metabolism has emerged as a promising strategy to overcome this barrier, with approaches including buffer agents to neutralize acidic pH and inhibitors to block lactate production or transport, thereby restoring immune cell efficacy in the TME. Recent discoveries have identified genes involved in extracellular pH (pHe) regulation, presenting new therapeutic targets. Moreover, ongoing research aims to elucidate the molecular mechanisms driving extracellular acidification and to develop treatments that modulate pH levels to enhance immunotherapy outcomes. Additionally, future clinical studies are crucial to validate the safety and efficacy of pHe-targeted therapies in cancer patients. Thus, this review explores the regulation of pHe in the TME and its potential role in improving cancer immunotherapy.

Keywords:  T cells; acidic TME; extracellular pH; immunotherapy resistance; lactate metabolism; tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/cells13221924