bims-mecami 2023-01-08 papers

Issue of 2023–01–08
seven papers selected by
Linda Chan, Cleveland Clinic

Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00546-0. [Epub ahead of print]35(1): 3-5

Early immune pressure makes tumors metabolically stronger.

Metabolic communication in the tumor microenvironment underscores tumor-immune interactions and affects anti-tumor immunity, yet cell-extrinsic signals driving tumor metabolic remodeling are incompletely understood. In this issue, Tsai et al. show that during initial tumorigenesis, T cell-derived IFNγ triggers STAT3 activation and c-Myc-dependent alterations of tumor cell metabolism, which potentiates immune evasion.

DOI: https://doi.org/10.1016/j.cmet.2022.12.009

Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00540-X. [Epub ahead of print]35(1): 118-133.e7

Immunoediting instructs tumor metabolic reprogramming to support immune evasion.

Immunoediting sculpts immunogenicity and thwarts host anti-tumor responses in tumor cells during tumorigenesis; however, it remains unknown whether metabolic programming of tumor cells can be guided by immunosurveillance. Here, we report that T cell-mediated immunosurveillance in early-stage tumorigenesis instructs c-Myc upregulation and metabolic reprogramming in tumor cells. This previously unexplored tumor-immune interaction is controlled by non-canonical interferon gamma (IFNγ)-STAT3 signaling and supports tumor immune evasion. Our findings uncover that immunoediting instructs deregulated bioenergetic programs in tumor cells to empower them to disarm the T cell-mediated immunosurveillance by imposing metabolic tug-of-war between tumor and infiltrating T cells and forming the suppressive tumor microenvironment.

Keywords: IFNγ; Myc; STAT3; immunoediting; immunosurveillance; tumor immunology

DOI: https://doi.org/10.1016/j.cmet.2022.12.003

Nat Rev Cancer. 2023 Jan 03.

STAT proteins in cancer: orchestration of metabolism.

Yi-Jia Li, Chunyan Zhang, Antons Martincuks, Andreas Herrmann, Hua Yu.

Reprogrammed metabolism is a hallmark of cancer. However, the metabolic dependency of cancer, from tumour initiation through disease progression and therapy resistance, requires a spectrum of distinct reprogrammed cellular metabolic pathways. These pathways include aerobic glycolysis, oxidative phosphorylation, reactive oxygen species generation, de novo lipid synthesis, fatty acid β-oxidation, amino acid (notably glutamine) metabolism and mitochondrial metabolism. This Review highlights the central roles of signal transducer and activator of transcription (STAT) proteins, notably STAT3, STAT5, STAT6 and STAT1, in orchestrating the highly dynamic metabolism not only of cancer cells but also of immune cells and adipocytes in the tumour microenvironment. STAT proteins are able to shape distinct metabolic processes that regulate tumour progression and therapy resistance by transducing signals from metabolites, cytokines, growth factors and their receptors; defining genetic programmes that regulate a wide range of molecules involved in orchestration of metabolism in cancer and immune cells; and regulating mitochondrial activity at multiple levels, including energy metabolism and lipid-mediated mitochondrial integrity. Given the central role of STAT proteins in regulation of metabolic states, they are potential therapeutic targets for altering metabolic reprogramming in cancer.

DOI: https://doi.org/10.1038/s41568-022-00537-3

Cancer Res. 2023 Jan 03. pii: CAN-22-2045. [Epub ahead of print]

Enhanced glutaminolysis drives hypoxia-induced chemoresistance in pancreatic cancer.

Seung Joon Park, Hee Chan Yoo, Eunyong Ahn, Enzhi Luo, Yeabeen Kim, Yulseung Sung, Ya Chun Yu, Kibum Kim, Do Sik Min, Hee Seung Lee, Geum-Sook Hwang, TaeJin Ahn, Junjeong Choi, Seungmin Bang, Jung Min Han.

Pancreatic ductal adenocarcinoma (PDAC) exhibits severe hypoxia, which is associated with chemoresistance and worse patient outcome. It has been reported that hypoxia induces metabolic reprogramming in cancer cells. However, it is not well known whether metabolic reprogramming contributes to hypoxia. Here, we established that increased glutamine catabolism is a fundamental mechanism inducing hypoxia, and thus chemoresistance, in PDAC cells. An extracellular matrix (ECM) component-based in vitro 3D cell printing model with patient-derived PDAC cells that recapitulates the hypoxic status in PDAC tumors showed that chemoresistant PDAC cells exhibit markedly enhanced glutamine catabolism compared to chemoresponsive PDAC cells. The augmented glutamine metabolic flux increased the oxygen consumption rate via mitochondrial oxidative phosphorylation (OXPHOS), promoting hypoxia and hypoxia-induced chemoresistance. Targeting glutaminolysis relieved hypoxia and improved chemotherapy efficacy in vitro and in vivo. This work suggests that targeting the glutaminolysis-OXPHOS-hypoxia axis is a novel therapeutic target for treating patients with chemoresistant PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-2045

Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00544-7. [Epub ahead of print]35(1): 5-7

Illuminating lactate in cells, mice, and patient samples.

Zefan Li, Hui-Wang Ai.

Lactate has emerged as a central metabolic fuel and an important signaling molecule. In this issue of Cell Metabolism, Li et al. develop a high-quality lactate sensor, allowing them to monitor lactate levels in cells, subcellular organelles, live mice, and human body fluids.

DOI: https://doi.org/10.1016/j.cmet.2022.12.007

Methods Mol Biol. 2023 ;2614 17-36

Analyzing the Tumor-Immune Microenvironment by Flow Cytometry.

François Santinon, Yoon Kow Young, Sonia V Del Rincón, Koren K Mann.

Flow cytometry is an essential tool for studying the tumor-immune microenvironment. It allows us to quickly quantify and identify multiple cell types in a heterogeneous sample. This chapter provides an overview of the flow cytometry instrumentation and a discussion of the appropriate considerations and steps in building a reproducible flow cytometry staining panel. We present an updated lymphoid tissue and solid tumor-infiltrating leucocyte flow cytometry staining protocol and an example of flow cytometry data analysis.

Keywords: Cell sorting; Compensation; Flow cytometry (FCM); Fluorescence minus one (FMO); Immune cell infiltrate; Intracellular staining; Isotype control; Multi-parameter; Solid tumor; Spillover; Staining panel; Tumor microenvironment

DOI: https://doi.org/10.1007/978-1-0716-2914-7_2

J Immunol. 2023 Jan 04. pii: ji2200325. [Epub ahead of print]

Glucose Requirement of Antigen-Specific Autoreactive B Cells and CD4+ T Cells.

Georges Abboud, Seung-Chul Choi, Xiaojuan Zhang, Yuk Pheel Park, Nathalie Kanda, Leilani Zeumer-Spataro, Morgan Terrell, Xiangyu Teng, Kirsten Nündel, Mark J Shlomchik, Laurence Morel.

The activation of lymphocytes in patients with lupus and in mouse models of the disease is coupled with an increased cellular metabolism in which glucose plays a major role. The pharmacological inhibition of glycolysis with 2-deoxy-d-glucose (2DG) reversed the expansion of follicular helper CD4+ T cells and germinal center B cells in lupus-prone mice, as well as the production of autoantibodies. The response of foreign Ags was however not affected by 2DG in these mice, suggesting that B and CD4+ T cell activation by autoantigens is uniquely sensitive to glycolysis. In this study, we tested this hypothesis with monoclonal B cells and CD4+ T cells specific for lupus-relevant autoantigens. AM14 Vκ8R (AM14) transgenic B cells are activated by IgG2a/chromatin immune complexes and they can receive cognate help from chromatin-specific 13C2 CD4+ T cells. We showed that activation of AM14 B cells by their cognate Ag PL2-3 induced glycolysis, and that the inhibition of glycolysis reduced their activation and differentiation into Ab-forming cells, in the absence or presence of T cell help. The dependency of autoreactive B cells on glycolysis is in sharp contrast with the previously reported dependency of 4-hydroxy-3-nitrophenyl acetyl-specific B cells on fatty acid oxidation. Contrary to AM14 B cells, the activation and differentiation of 13C2 T cells into follicular helper CD4+ T cells was not altered by 2DG, which differs from polyclonal CD4+ T cells from lupus-prone mice. These results further define the role of glycolysis in the production of lupus autoantibodies and demonstrate the need to evaluate the metabolic requirements of Ag-specific B and T cells.

DOI: https://doi.org/10.4049/jimmunol.2200325