bims-mecami 2023-06-11 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2023‒06‒11
eight papers selected by
Oltea Sampetrean, Keio University

Fumarate disarms CD8+ T cells against cancer.
Crosstalk between arginine, glutamine, and the branched chain amino acid metabolism in the tumor microenvironment.
Uptake of long-chain fatty acids from the bone marrow suppresses CD8+ T-cell metabolism and function in multiple myeloma.
Tumor cell-derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8+ T cell activation.
Amino Acid Metabolism in Bone Metastatic Disease.
Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy.
Reshaping immunometabolism in the tumour microenvironment to improve cancer immunotherapy.
Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity.

Cell Metab. 2023 Jun 06. pii: S1550-4131(23)00182-1. [Epub ahead of print]35(6): 907-909

Fumarate disarms CD8+ T cells against cancer.

Luigi Nezi, Teresa Manzo.

The composition of nutrients in the tumor microenvironment is a key determinant of anti-tumor CD8+ T cell response. In this issue of Cell Metabolism, Jiang and colleagues unveil that tumor-derived fumarate dampens TCR signaling in CD8+ T cells, resulting in defective activation, loss of effector functions, and associated failure of tumor control.

DOI: https://doi.org/10.1016/j.cmet.2023.05.005
Front Oncol. 2023 ;13 1186539

Crosstalk between arginine, glutamine, and the branched chain amino acid metabolism in the tumor microenvironment.

Tanner J Wetzel, Sheila C Erfan, Lucas D Figueroa, Leighton M Wheeler, Elitsa A Ananieva.

  Arginine, glutamine, and the branched chain amino acids (BCAAs) are a focus of increased interest in the field of oncology due to their importance in the metabolic reprogramming of cancer cells. In the tumor microenvironment (TME), these amino acids serve to support the elevated biosynthetic and energy demands of cancer cells, while simultaneously maintaining the growth, homeostasis, and effector function of tumor-infiltrating immune cells. To escape immune destruction, cancer cells utilize a variety of mechanisms to suppress the cytotoxic activity of effector T cells, facilitating T cell exhaustion. One such mechanism is the ability of cancer cells to overexpress metabolic enzymes specializing in the catabolism of arginine, glutamine, and the BCAAs in the TME. The action of such enzymes supplies cancer cells with metabolic intermediates that feed into the TCA cycle, supporting energy generation, or providing precursors for purine, pyrimidine, and polyamine biosynthesis. Armed with substantial metabolic flexibility, cancer cells redirect amino acids from the TME for their own advantage and growth, while leaving the local infiltrating effector T cells deprived of essential nutrients. This review addresses the metabolic pressure that cancer cells exert over immune cells in the TME by up-regulating amino acid metabolism, while discussing opportunities for targeting amino acid metabolism for therapeutic intervention. Special emphasis is given to the crosstalk between arginine, glutamine, and BCAA metabolism in affording cancer cells with metabolic dominance in the TME.

Keywords:  TME; arginine; glutamine; isoleucine; leucine; metabolism; valine

DOI:  https://doi.org/10.3389/fonc.2023.1186539
Blood Adv. 2023 Jun 05. pii: bloodadvances.2023009890. [Epub ahead of print]

Uptake of long-chain fatty acids from the bone marrow suppresses CD8+ T-cell metabolism and function in multiple myeloma.

Nancy Gudgeon, Hannah Victoria Giles, Emma Louise Bishop, Taylor Fulton-Ward, Cristina Escribano-Gonzalez, Haydn Munford, Anna James-Bott, Kane Foster, Farheen Karim, Dedunu Abeysekara Jayawardana, Ansar Mahmood, Adam Cribbs, Daniel A Tennant, Supratik Basu, Guy Pratt, Sarah Dimeloe.

T cells demonstrate impaired function in Multiple Myeloma (MM), but suppressive mechanisms in the bone marrow microenvironment remain poorly defined. We observe that bone marrow CD8+ T-cell function is decreased in MM patients compared to controls, and also is consistently lower within bone marrow samples than matched peripheral blood. These changes are accompanied by decreased mitochondrial mass and markedly elevated long-chain fatty acid uptake. In vitro modelling confirmed that uptake of bone marrow lipids suppresses CD8+ T function, which is impaired in autologous bone marrow plasma, but rescued by lipid removal. Analysis of single-cell RNA-sequencing data identified expression of fatty acid transport protein 1 (FATP1) in bone marrow CD8+ T cells in MM, and FATP1 blockade also rescued CD8+ T-cell function, thereby identifying this as a novel target to augment T cell activity in MM. Finally, analysis of samples from treated patient cohorts identified that CD8+ T cell metabolic dysfunction resolves in treatment-responsive but not relapsed MM patients and is associated with substantial T cell functional restoration.

DOI: https://doi.org/10.1182/bloodadvances.2023009890
Proc Natl Acad Sci U S A. 2023 Jun 13. 120(24): e2305245120

Tumor cell-derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8+ T cell activation.

Sana Hibino, Shotaro Eto, Sho Hangai, Keiko Endo, Sanae Ashitani, Maki Sugaya, Tsuyoshi Osawa, Tomoyoshi Soga, Tadatsugu Taniguchi, Hideyuki Yanai.

  The activation and expansion of T cells that recognize cancer cells is an essential aspect to antitumor immunity. Tumors may escape destruction by the immune system through ectopic expression of inhibitory immune ligands typically exemplified by the PD-L1/PD-1 pathway. Here, we reveal another facet of tumor evasion from T cell surveillance. By secretome profiling of necrotic tumor cells, we identified an oncometabolite spermidine as a unique inhibitor of T cell receptor (TCR) signaling. Mechanistically, spermidine causes the downregulation of the plasma membrane cholesterol levels, resulting in the suppression of TCR clustering. Using syngeneic mouse models, we show that spermidine is abundantly detected in the tumor immune microenvironment (TIME) and that administration of the polyamine synthesis inhibitor effectively enhanced CD8+ T cell-dependent antitumor responses. Further, the combination of the polyamine synthesis inhibitor with anti-PD-1 immune checkpoint antibody resulted in a much stronger antitumor immune response. This study reveals an aspect of immunosuppressive TIME, wherein spermidine functions as a metabolic T cell checkpoint that may offer a unique approach for promoting tumor immunotherapy.

Keywords:  T cell; cancer immunotherapy; cell death; oncometabolite; spermidine

DOI:  https://doi.org/10.1073/pnas.2305245120
Curr Osteoporos Rep. 2023 Jun 06.

Amino Acid Metabolism in Bone Metastatic Disease.

Deanna N Edwards.

  PURPOSE OF REVIEW: Breast and prostate tumors frequently metastasize to the bone, but the underlying mechanisms for osteotropism remain elusive. An emerging feature of metastatic progression is metabolic adaptation of cancer cells to new environments. This review will summarize the recent advances on how cancer cells utilize amino acid metabolism during metastasis, from early dissemination to interactions with the bone microenvironment.RECENT FINDINGS: Recent studies have suggested that certain metabolic preferences for amino acids may be associated with bone metastasis. Once in the bone microenvironment, cancer cells encounter a favorable microenvironment, where a changing nutrient composition of the tumor-bone microenvironment may alter metabolic interactions with bone-resident cells to further drive metastatic outgrowth. Enhanced amino acid metabolic programs are associated with bone metastatic disease and may be further augmented by the bone microenvironment. Additional studies are necessary to fully elucidate the role of amino acid metabolism on bone metastasis.

Keywords:  Amino acids; Bone; Cancer; Metabolism; Metastasis; Microenvironment

DOI:  https://doi.org/10.1007/s11914-023-00797-4
J Hematol Oncol. 2023 Jun 05. 16(1): 59

Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy.

Luming Yang, Zhaole Chu, Meng Liu, Qiang Zou, Jinyang Li, Qin Liu, Yazhou Wang, Tao Wang, Junyu Xiang, Bin Wang.

  Amino acids are basic nutrients for immune cells during organ development, tissue homeostasis, and the immune response. Regarding metabolic reprogramming in the tumor microenvironment, dysregulation of amino acid consumption in immune cells is an important underlying mechanism leading to impaired anti-tumor immunity. Emerging studies have revealed that altered amino acid metabolism is tightly linked to tumor outgrowth, metastasis, and therapeutic resistance through governing the fate of various immune cells. During these processes, the concentration of free amino acids, their membrane bound transporters, key metabolic enzymes, and sensors such as mTOR and GCN2 play critical roles in controlling immune cell differentiation and function. As such, anti-cancer immune responses could be enhanced by supplement of specific essential amino acids, or targeting the metabolic enzymes or their sensors, thereby developing novel adjuvant immune therapeutic modalities. To further dissect metabolic regulation of anti-tumor immunity, this review summarizes the regulatory mechanisms governing reprogramming of amino acid metabolism and their effects on the phenotypes and functions of tumor-infiltrating immune cells to propose novel approaches that could be exploited to rewire amino acid metabolism and enhance cancer immunotherapy.

Keywords:  Amino acids; Immune cells; SLC transporters; Tumor microenvironment; mTOR

DOI:  https://doi.org/10.1186/s13045-023-01453-1
Biomed Pharmacother. 2023 Jun 01. pii: S0753-3322(23)00753-9. [Epub ahead of print]164 114963

Reshaping immunometabolism in the tumour microenvironment to improve cancer immunotherapy.

Shuchen Chen, He Duan, Gongping Sun.

  The evolving understanding of cellular metabolism has revealed a the promise of strategies aiming to modulate anticancer immunity by targeting metabolism. The combination of metabolic inhibitors with immune checkpoint blockade (ICB), chemotherapy and radiotherapy may offer new approaches to cancer treatment. However, it remains unclear how these strategies can be better utilized despite the complex tumour microenvironment (TME). Oncogene-driven metabolic changes in tumour cells can affect the TME, limiting the immune response and creating many barriers to cancer immunotherapy. These changes also reveal opportunities to reshape the TME to restore immunity by targeting metabolic pathways. Further exploration is required to determine how to make better use of these mechanistic targets. Here, we review the mechanisms by which tumour cells reshape the TME and cause immune cells to transition into an abnormal state by secreting multiple factors, with the ultimate goal of proposing targets and optimizing the use of metabolic inhibitors. Deepening our understanding of changes in metabolism and immune function in the TME will help advance this promising field and enhance immunotherapy.

Keywords:  Diet; Immunometabolism; Immunotherapy; Lactate; Tumour microenvironment

DOI:  https://doi.org/10.1016/j.biopha.2023.114963
Nat Commun. 2023 Jun 03. 14(1): 3214

Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity.

Jacqueline A Turner, Malia A Fredrickson, Marc D'Antonio, Elizabeth Katsnelson, Morgan MacBeth, Robert Van Gulick, Tugs-Saikhan Chimed, Martin McCarter, Angelo D'Alessandro, William A Robinson, Kasey L Couts, Roberta Pelanda, Jared Klarquist, Richard P Tobin, Raul M Torres.

Lysophosphatidic acid (LPA) is a bioactive lipid which increases in concentration locally and systemically across different cancer types. Yet, the exact mechanism(s) of how LPA affects CD8 T cell immunosurveillance during tumor progression remain unknown. We show LPA receptor (LPAR) signaling by CD8 T cells promotes tolerogenic states via metabolic reprogramming and potentiating exhaustive-like differentiation to modulate anti-tumor immunity. We found LPA levels predict response to immunotherapy and Lpar5 signaling promotes cellular states associated with exhausted phenotypes on CD8 T cells. Importantly, we show that Lpar5 regulates CD8 T cell respiration, proton leak, and reactive oxygen species. Together, our findings reveal that LPA serves as a lipid-regulated immune checkpoint by modulating metabolic efficiency through LPAR5 signaling on CD8 T cells. Our study offers key insights into the mechanisms governing adaptive anti-tumor immunity and demonstrates LPA could be exploited as a T cell directed therapy to improve dysfunctional anti-tumor immunity.

DOI: https://doi.org/10.1038/s41467-023-38933-4