bims-mecami 2024-11-03 papers

Issue of 2024–11–03
six papers selected by
Oltea Sampetrean, Keio University

Int Immunopharmacol. 2024 Oct 24. pii: S1567-5769(24)01934-9. [Epub ahead of print]143(Pt 2): 113412

Targeting metabolic pathway enhance CAR-T potency for solid tumor.

Chimeric antigen receptor (CAR) T cells have great potential in cancer therapy, particularly in treating hematologic malignancies. However, their efficacy in solid tumors remains limited, with a significant proportion of patients failing to achieve long-term complete remission. One major challenge is the premature exhaustion of CAR-T cells, often due to insufficient metabolic energy. The survival, function and metabolic adaptation of CAR-T cells are key determinants of their therapeutic efficacy. We explore how targeting metabolic pathways in the tumor microenvironment can enhance CAR-T cell therapy by addressing metabolic competition and immunosuppression that impair CAR-T cell function. Tumors undergo metabolically reprogrammed to meet their rapid proliferation, thereby modulating metabolic pathways in immune cells to promote immunosuppression. The distinct metabolic requirements of tumors and T cells create a competitive environment, affecting the efficacy of CAR-T cell therapy. Recent research on glucose, lipid and amino acid metabolism, along with the interactions between tumor and immune cell metabolism, has revealed that targeting these metabolic processes can enhance antitumor immune responses. Combining metabolic interventions with existing antitumor therapies can fulfill the metabolic demands of immune cells, providing new ideas for tumor immunometabolic therapies. This review discusses the latest advances in the immunometabolic mechanisms underlying tumor immunosuppression, their implications for immunotherapy, and summarizes potential metabolic targets to improve the efficacy of CAR-T therapy.

Keywords: CAR-T cell therapy; Immunotherapy; Metabolism reprogramming; Tumor microenvironment

DOI: https://doi.org/10.1016/j.intimp.2024.113412

Cell Death Dis. 2024 Oct 26. 15(10): 775

Metabolic gatekeepers: harnessing tumor-derived metabolites to optimize T cell-based immunotherapy efficacy in the tumor microenvironment.

Yucheng Zheng, Rongwei Xu, Xu Chen, Ye Lu, Jiarong Zheng, Yunfan Lin, Pei Lin, Xinyuan Zhao, Li Cui.

The tumor microenvironment (TME) orchestrates a complex interplay between tumor cells and immune cells, crucially modulating the immune response. This review delves into the pivotal role of metabolic reprogramming in the TME, highlighting how tumor-derived metabolites influence T lymphocyte functionality and the efficacy of cancer immunotherapies. Focusing on the diverse roles of these metabolites, we examine how lactate, lipids, amino acids, and other biochemical signals act not only as metabolic byproducts but as regulatory agents that can suppress or potentiate T cell-mediated immunity. By integrating recent findings, we underscore the dual impact of these metabolites on enhancing tumor progression and inhibiting immune surveillance. Furthermore, we propose innovative therapeutic strategies that target metabolic pathways to restore immune function within the TME. The insights provided in this review pave the way for the development of metabolic interventions aimed at enhancing the success of immunotherapies in oncology, offering new hope for precision medicine in the treatment of cancer.

DOI: https://doi.org/10.1038/s41419-024-07122-6

Immunology. 2024 Oct 27.

Metabolic Reprogramming in Cancer: Implications for Immunosuppressive Microenvironment.

Durre Aden, Niti Sureka, Samreen Zaheer, Jai Kumar Chaurasia, Sufian Zaheer.

Cancer is a complex and heterogeneous disease characterised by uncontrolled cell growth and proliferation. One hallmark of cancer cells is their ability to undergo metabolic reprogramming, which allows them to sustain their rapid growth and survival. This metabolic reprogramming creates an immunosuppressive microenvironment that facilitates tumour progression and evasion of the immune system. In this article, we review the mechanisms underlying metabolic reprogramming in cancer cells and discuss how these metabolic alterations contribute to the establishment of an immunosuppressive microenvironment. We also explore potential therapeutic strategies targeting metabolic vulnerabilities in cancer cells to enhance immune-mediated anti-tumour responses. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02044861, NCT03163667, NCT04265534, NCT02071927, NCT02903914, NCT03314935, NCT03361228, NCT03048500, NCT03311308, NCT03800602, NCT04414540, NCT02771626, NCT03994744, NCT03229278, NCT04899921.

Keywords: cancer; immunosuppressive microenvironment; metabolic reprogramming

DOI: https://doi.org/10.1111/imm.13871

Clin Transl Radiat Oncol. 2024 Nov;49 100875

Inhibition of OXPHOS induces metabolic rewiring and reduces hypoxia in murine tumor models.

Daan F Boreel, Anne P M Beerkens, Sandra Heskamp, Milou Boswinkel, Johannes P W Peters, Gosse J Adema, Paul N Span, Johan Bussink.

Introduction: Tumor hypoxia is a feature of many solid malignancies and is known to cause radio resistance. In recent years it has become clear that hypoxic tumor regions also foster an immunosuppressive phenotype and are involved in immunotherapy resistance. It has been proposed that reducing the tumors' oxygen consumption will result in an increased oxygen concentration in the tissue and improve radio- and immunotherapy efficacy. The aim of this study is to investigate the metabolic rewiring of cancer cells by pharmacological attenuation of oxidative phosphorylation (OXPHOS) and subsequently reduce tumor hypoxia.
Material and methods: The metabolic effects of three OXPHOS inhibitors IACS-010759, atovaquone and metformin were explored by measuring oxygen consumption rate, extra cellular acidification rate, and [18F]FDG uptake in 2D and 3D cell culture. Tumor cell growth in 2D cell culture and hypoxia in 3D cell culture were analyzed by live cell imaging. Tumor hypoxia and [18F]FDG uptake in vivo following treatment with IACS-010759 was determined by immunohistochemistry and ex vivo biodistribution respectively.
Results: In vitro experiments show that tumor cell metabolism is heterogeneous between different models. Upon OXPHOS inhibition, metabolism shifts from oxygen consumption through OXPHOS towards glycolysis, indicated by increased acidification and glucose uptake. Inhibition of OXPHOS by IACS-010759 treatment reduced diffusion limited tumor hypoxia in both 3D cell culture and in vivo. Although immune cell presence was lower in hypoxic areas compared with normoxic areas, it is not altered following short term OXPHOS inhibition.
Discussion: These results show that inhibition of OXPHOS causes a metabolic shift from OXPHOS towards increased glycolysis in 2D and 3D cell culture. Moreover, inhibition of OXPHOS reduces diffusion limited hypoxia in 3D cell culture and murine tumor models. Reduced hypoxia by OXPHOS inhibition might enhance therapy efficacy in future studies. However, caution is warranted as systemic metabolic rewiring can cause adverse effects.

Keywords: Atovaquone; Hypoxia; IACS-010759; Metabolism; Metformin; OXPHOS

DOI: https://doi.org/10.1016/j.ctro.2024.100875

Trends Cell Biol. 2024 Oct 26. pii: S0962-8924(24)00206-X. [Epub ahead of print]

Sugar symphony: glycosylation in cancer metabolism and stemness.

Venkatesh Varadharaj, Wyatt Petersen, Surinder K Batra, Moorthy P Ponnusamy.

Glycosylation is a complex co-translational and post-translational modification (PTM) in eukaryotes that utilizes glycosyltransferases to generate a vast array of glycoconjugate structures. Recent studies have highlighted the role of glycans in regulating essential molecular, cellular, tissue, organ, and systemic biological processes with significant implications for human diseases, particularly cancer. The metabolic reliance of cancer, spanning tumor initiation, disease progression, and resistance to therapy, necessitates a range of uniquely altered cellular metabolic pathways. In addition, the intricate interplay between cell-intrinsic and -extrinsic mechanisms is exemplified by the communication between cancer cells, cancer stem cells (CSCs), cancer-associated fibroblasts (CAFs), and immune cells within the tumor microenvironment (TME). In this review article, we explore how differential glycosylation in cancer influences the metabolism and stemness features alongside new avenues in glycobiology.

Keywords: glycoconjugate; glycosyltransferase; metabolism; stemness

DOI: https://doi.org/10.1016/j.tcb.2024.09.006

Int Immunopharmacol. 2024 Oct 28. pii: S1567-5769(24)01992-1. [Epub ahead of print]143(Pt 2): 113470

Colorectal cancer cells establish metabolic reprogramming with cancer-associated fibroblasts (CAFs) through lactate shuttle to enhance invasion, migration, and angiogenesis.

Xingchen Wang, Yaru Qu, Jianbo Ji, He Liu, Huiyuan Luo, Junnan Li, Xiuzhen Han.

Fibroblasts undergo metabolic reprogramming after contact with cancer cells in tumor microenvironment, producing lactate to provide a metabolic substrate for neighboring tumor cells. The exchange of lactate between cancer cells and fibroblasts via monocarboxylate transporters (MCTs) is known as the lactate shuttle. Colorectal cancer cells may establish a metabolic coupling akin to the lactate shuttle in collaboration with cancer-associated fibroblasts (CAFs) to augment their invasive and migratory capabilities. However, the specific phenomena and underlying mechanisms are not clear. In this study, we investigated the phenomena and explored the correlation and possible mechanism between CAFs and the invasion and migration of colorectal cancer cells by using two different co-culture models. The results showed that colorectal cancer cells established a lactate metabolic coupling with fibroblasts through the oxidative stress effect, triggering the metabolic reprogramming process of themselves and those of fibroblasts. In addition, lactate enhanced the invasion and migration of colorectal cancer by stabilizing the protein expression levels of nuclear factor kappa-B (NF-κB) and hypoxia-inducible factor-1α (HIF-1α). Blocking oxidative stress and lactate metabolic coupling with reactive oxygen species removers and MCT1-specific inhibitors, respectively, could effectively suppress metastasis in colorectal cancer. These findings suggest that targeting the lactate metabolic coupling between tumor cells and CAFs will offer a new strategy to combat colorectal cancer.

Keywords: CAFs; Lactate shuttle; MCT1; Metabolic reprogramming; Tumor microenvironment

DOI: https://doi.org/10.1016/j.intimp.2024.113470