bims-stacyt 2022-01-02 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2022–01–02
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Neutrophil metabolism in the cancer context.
Neutrophil and Natural Killer Cell Interactions in Cancers: Dangerous Liaisons Instructing Immunosuppression and Angiogenesis.
Macrophages are metabolically heterogeneous within the tumor microenvironment.
Arginine and Arginases Modulate Metabolism, Tumor Microenvironment and Prostate Cancer Progression.
Impact of cancer metabolism on therapy resistance - Clinical implications.
Glutamine promotes the generation of B10+ cells via the mTOR/GSK3 pathway.
Glucocorticoids Coordinate Macrophage Metabolism Through Regulation of the Tricarboxylic Acid Cycle.
Hypoxia promotes the tolerogenic phenotype of plasmacytoid dendritic cells in head and neck squamous cell carcinoma.
Metabolic manipulation of the tumour immune microenvironment.
EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion.

Semin Immunol. 2021 Dec 25. pii: S1044-5323(21)00114-7. [Epub ahead of print] 101583

Neutrophil metabolism in the cancer context.

Anita Bodac, Etienne Meylan.

  Neutrophils are critical innate immune cells for the host anti-bacterial defense. Throughout their lifecycle, neutrophils are exposed to different microenvironments and modulate their metabolism to survive and sustain their functions. Although tumor cell metabolism has been intensively investigated, how neutrophil metabolism is affected in cancer remains largely to be discovered. Neutrophils are described as mainly glycolytic cells. However, distinct tumor-associated neutrophil (TAN) states may co-exist in tumors and adapt their metabolism to exert different or even opposing activities ranging from tumor cell killing to tumor support. In this review, we gather evidence about the metabolic mechanisms that underly TANs' pro- or anti-tumoral functions in cancer. We first discuss how tumor-secreted factors and the heterogenous tumor microenvironment can have a strong impact on TAN metabolism. We then describe alternative metabolic pathways used by TANs to exert their functions in cancer, from basic glycolysis to more recently-recognized but less understood metabolic shifts toward mitochondrial oxidative metabolism, lipid and amino acid metabolism and even autophagy. Last, we discuss promising strategies targeting neutrophil metabolism to combat cancer.

Keywords:  Cancer metabolism; Neutrophil metabolism; Tumor-associated neutrophils

DOI:  https://doi.org/10.1016/j.smim.2021.101583
Vaccines (Basel). 2021 Dec 16. pii: 1488. [Epub ahead of print]9(12):

Neutrophil and Natural Killer Cell Interactions in Cancers: Dangerous Liaisons Instructing Immunosuppression and Angiogenesis.

Maria Teresa Palano, Matteo Gallazzi, Martina Cucchiara, Andrea De Lerma Barbaro, Daniela Gallo, Barbara Bassani, Antonino Bruno, Lorenzo Mortara.

  The tumor immune microenvironment (TIME) has largely been reported to cooperate on tumor onset and progression, as a consequence of the phenotype/functional plasticity and adaptation capabilities of tumor-infiltrating and tumor-associated immune cells. Immune cells within the tumor micro (tissue-local) and macro (peripheral blood) environment closely interact by cell-to-cell contact and/or via soluble factors, also generating a tumor-permissive soil. These dangerous liaisons have been investigated for pillars of tumor immunology, such as tumor associated macrophages and T cell subsets. Here, we reviewed and discussed the contribution of selected innate immunity effector cells, namely neutrophils and natural killer cells, as "soloists" or by their "dangerous liaisons", in favoring tumor progression by dissecting the cellular and molecular mechanisms involved.

Keywords:  immunosuppression; natural killer cells; neutrophil-NK cell crosstalk; neutrophils; tumor angiogenesis; tumor microenvironment

DOI:  https://doi.org/10.3390/vaccines9121488
Cell Rep. 2021 Dec 28. pii: S2211-1247(21)01671-5. [Epub ahead of print]37(13): 110171

Macrophages are metabolically heterogeneous within the tumor microenvironment.

Xenia Geeraerts, Juan Fernández-Garcia, Felix J Hartmann, Kyra E de Goede, Liesbet Martens, Yvon Elkrim, Ayla Debraekeleer, Benoit Stijlemans, Anke Vandekeere, Gianmarco Rinaldi, Riet De Rycke, Mélanie Planque, Dorien Broekaert, Elisa Meinster, Emile Clappaert, Pauline Bardet, Aleksandar Murgaski, Conny Gysemans, Frank Aboubakar Nana, Yvan Saeys, Sean C Bendall, Damya Laoui, Jan Van den Bossche, Sarah-Maria Fendt, Jo A Van Ginderachter.

  Macrophages are often prominently present in the tumor microenvironment, where distinct macrophage populations can differentially affect tumor progression. Although metabolism influences macrophage function, studies on the metabolic characteristics of ex vivo tumor-associated macrophage (TAM) subsets are rather limited. Using transcriptomic and metabolic analyses, we now reveal that pro-inflammatory major histocompatibility complex (MHC)-IIhi TAMs display a hampered tricarboxylic acid (TCA) cycle, while reparative MHC-IIlo TAMs show higher oxidative and glycolytic metabolism. Although both TAM subsets rapidly exchange lactate in high-lactate conditions, only MHC-IIlo TAMs use lactate as an additional carbon source. Accordingly, lactate supports the oxidative metabolism in MHC-IIlo TAMs, while it decreases the metabolic activity of MHC-IIhi TAMs. Lactate subtly affects the transcriptome of MHC-IIlo TAMs, increases L-arginine metabolism, and enhances the T cell suppressive capacity of these TAMs. Overall, our data uncover the metabolic intricacies of distinct TAM subsets and identify lactate as a carbon source and metabolic and functional regulator of TAMs.

Keywords:  TCA cycle break; immunometabolism; immunosuppression; lactate; macrophage metabolism; metabolomics; non-small-cell lung carcinoma; single-cell metabolic profiling; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.celrep.2021.110171
Nutrients. 2021 Dec 16. pii: 4503. [Epub ahead of print]13(12):

Arginine and Arginases Modulate Metabolism, Tumor Microenvironment and Prostate Cancer Progression.

Andreia Matos, Marcos Carvalho, Manuel Bicho, Ricardo Ribeiro.

  Arginine availability and activation of arginine-related pathways at cancer sites have profound effects on the tumor microenvironment, far beyond their well-known role in the hepatic urea cycle. Arginine metabolism impacts not only malignant cells but also the surrounding immune cells behavior, modulating growth, survival, and immunosurveillance mechanisms, either through an arginase-mediated effect on polyamines and proline synthesis, or by the arginine/nitric oxide pathway in tumor cells, antitumor T-cells, myeloid-derived suppressor cells, and macrophages. This review presents evidence concerning the impact of arginine metabolism and arginase activity in the prostate cancer microenvironment, highlighting the recent advances in immunotherapy, which might be relevant for prostate cancer. Even though further research is required, arginine deprivation may represent a novel antimetabolite strategy for the treatment of arginine-dependent prostate cancer.

Keywords:  arginase; arginine; metabolism; nitric oxide; prostate cancer; tumor microenvironment

DOI:  https://doi.org/10.3390/nu13124503
Drug Resist Updat. 2021 Dec 16. pii: S1368-7646(21)00057-1. [Epub ahead of print] 100797

Impact of cancer metabolism on therapy resistance - Clinical implications.

Ana Cristina Gonçalves, Elena Richiardone, Joana Jorge, Bárbara Polónia, Cristina P R Xavier, Iris Chiara Salaroglio, Chiara Riganti, M Helena Vasconcelos, Cyril Corbet, Ana Bela Sarmento-Ribeiro.

  Despite an increasing arsenal of anticancer therapies, many patients continue to have poor outcomes due to the therapeutic failures and tumor relapses. Indeed, the clinical efficacy of anticancer therapies is markedly limited by intrinsic and/or acquired resistance mechanisms that can occur in any tumor type and with any treatment. Thus, there is an urgent clinical need to implement fundamental changes in the tumor treatment paradigm by the development of new experimental strategies that can help to predict the occurrence of clinical drug resistance and to identify alternative therapeutic options. Apart from mutation-driven resistance mechanisms, tumor microenvironment (TME) conditions generate an intratumoral phenotypic heterogeneity that supports disease progression and dismal outcomes. Tumor cell metabolism is a prototypical example of dynamic, heterogeneous, and adaptive phenotypic trait, resulting from the combination of intrinsic [(epi)genetic changes, tissue of origin and differentiation dependency] and extrinsic (oxygen and nutrient availability, metabolic interactions within the TME) factors, enabling cancer cells to survive, metastasize and develop resistance to anticancer therapies. In this review, we summarize the current knowledge regarding metabolism-based mechanisms conferring adaptive resistance to chemo-, radio-and immunotherapies as well as targeted therapies. Furthermore, we report the role of TME-mediated intratumoral metabolic heterogeneity in therapy resistance and how adaptations in amino acid, glucose, and lipid metabolism support the growth of therapy-resistant cancers and/or cellular subpopulations. We also report the intricate interplay between tumor signaling and metabolic pathways in cancer cells and discuss how manipulating key metabolic enzymes and/or providing dietary changes may help to eradicate relapse-sustaining cancer cells. Finally, in the current era of personalized medicine, we describe the strategies that may be applied to implement metabolic profiling for tumor imaging, biomarker identification, selection of tailored treatments and monitoring therapy response during the clinical management of cancer patients.

Keywords:  Cancer metabolism; Glycolysis; Intratumor heterogeneity; Metabolic plasticity; Oxidative phosphorylation; Therapy resistance; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.drup.2021.100797
Eur J Immunol. 2021 Dec 27.

Glutamine promotes the generation of B10+ cells via the mTOR/GSK3 pathway.

Julie Mielle, Jacques Morel, Jamila ElHmioui, Bernard Combe, Laurence Macia, Valérie Dardalhon, Naomi Taylor, Rachel Audo, Claire Daien.

  Alterations in cell metabolism can shift the differentiation of immune cells towards a regulatory or inflammatory phenotype, thus opening up new therapeutic opportunities for immune-related diseases. Indeed, growing knowledge on T cell metabolism has revealed differences in the metabolic programs of suppressive regulatory T cells (Tregs) as compared to inflammatory Th1 and Th17 cells. In addition to Tregs, IL-10-producing regulatory B cells are crucial for maintaining tolerance, inhibiting inflammation and autoimmunity. Yet, the metabolic networks regulating diverse B lymphocyte responses are not well known. Here, we show that glutaminase blockade decreased downstream mTOR activation and attenuated IL-10 secretion. Direct suppression of mTOR activity by rapamycin selectively impaired IL-10 production by B cells whereas secretion was restored upon GSK3 inhibition. Mechanistically, we found mTORC1 activation leads to GSK3 inhibition, identifying a key signalling pathway regulating IL-10 secretion by B lymphocytes. Thus, our results identify glutaminolysis and the mTOR/GSK3 signalling axis, as critical regulators of the generation of IL-10 producing B cells with regulatory functions. This article is protected by copyright. All rights reserved.

Keywords:  B10; GSK3; IL-10; glutamine; immunotherapy; mTOR; metabolism; regulatory B cells

DOI:  https://doi.org/10.1002/eji.202149387
Mol Metab. 2021 Dec 22. pii: S2212-8778(21)00282-9. [Epub ahead of print] 101424

Glucocorticoids Coordinate Macrophage Metabolism Through Regulation of the Tricarboxylic Acid Cycle.

Ulrich Stifel, Eva-Maria Wolfschmitt, Josef Vogt, Ulrich Wachter, Sabine Vettorazzi, Daniel Tews, Melanie Hogg, Fabian Zink, Nora Maria Koll, Sandra Winning, Rémi Mounier, Bénédicte Chazaud, Peter Radermacher, Pamela Fischer-Posovszky, Giorgio Caratti, Jan Tuckermann.

  Glucocorticoids (GCs) are one of the most widely prescribed anti-inflammatory drugs. By acting through their cognate receptor, the glucocorticoid receptor (GR), GCs down-regulate the expression of pro-inflammatory genes, and up-regulate anti-inflammatory genes. Metabolic pathways have recently been identified as key parts of both the inflammatory activation and anti-inflammatory polarization of macrophages, immune cells responsible for acute inflammation and tissue repair. It is currently unknown whether GCs control macrophage metabolism, and if so, to what extent metabolic regulation by GCs confers anti-inflammatory activity. Using transcriptomic and metabolomic profiling of macrophages, we identified GC controlled pathways involved in metabolism, especially in mitochondrial function. Metabolic analyses revealed that GCs repress glycolysis in inflammatory myeloid cells and promote tricarboxylic acid (TCA) cycle flux, promoting succinate metabolism and preventing intracellular accumulation of succinate. Inhibition of ATP synthase attenuated GC induced transcriptional changes, likely through stalling of TCA cycle anaplerosis. We further identified a glycolytic regulatory transcription factor, HIF1α, as regulated by GCs, and as a key regulator of GC responsiveness during inflammatory challenge, further linking metabolism to GC action in macrophages.

Keywords:  Glucocorticoids; Succinate; TCA Cycle; immunometabolism; macrophage

DOI:  https://doi.org/10.1016/j.molmet.2021.101424
Cancer Med. 2021 Dec 28.

Hypoxia promotes the tolerogenic phenotype of plasmacytoid dendritic cells in head and neck squamous cell carcinoma.

Cui Fan, Jichang Wu, Yilin Shen, Haixia Hu, Quan Wang, Yufeng Mao, Bin Ye, Mingliang Xiang.

   OBJECTIVE: We aim to review the roles of plasmacytoid dendritic cells (pDCs) in head and neck squamous cell carcinoma (HNSCC) and explore the effects of hypoxia on the tolerogenic transformation of pDCs.
BACKGROUND: pDCs, best known as professional type I interferon-secreting cells, play key roles in immune surveillance and antitumor immunity. Recently, pDCs have been shown to be tolerogenic and correlate with poor prognosis in a variety of cancers, including HNSCC. However, it remains unclear what drives the tolerogenic transformation of pDCs in the HNSCC microenvironment. Hypoxia, a prominent hallmark of the tumor microenvironment (TME) of HNSCC, can interfere with multiple immune cells and establish an immunosuppressive TME.
METHODS: In this review, we summarize the antitumor and protumor functions of pDCs, explore the effects of hypoxia on the migration and maturation of pDCs, and discuss related mechanisms in HNSCC.
CONCLUSIONS: pDCs mainly display protumor functions in HNSCC. The hypoxic TME in HNSCC can enhance the migration of pDCs and inhibit the differentiation and maturation of pDCs, promoting the tolerogenic phenotype of pDCs.

Keywords:  head and neck squamous cell carcinoma; hypoxia; immune suppression; plasmacytoid dendritic cells

DOI:  https://doi.org/10.1002/cam4.4511
Immunology. 2021 Dec 28.

Metabolic manipulation of the tumour immune microenvironment.

Mengtian Wan, Yuzhu Ding, Zheng Li, Xu Wang, Min Xu.

  In the past few years, the evolution of immunotherapy has resulted in a shift in cancer treatment models. However, with immunosuppressive effects of the tumour microenvironment continue to limit advances in tumour immunotherapy. The tumour microenvironment induces metabolic reprogramming in cancer cells, which results in competition for nutrients between tumour cells and host immunocytes. Metabolic and waste products originating in tumour cells can influence the activation and effector properties of immunocytes in numerous ways and ultimately promote the survival and propagation of tumour cells. In this paper, we discuss metabolic reprogramming in tumour cells and the influence of metabolite byproducts on the immune microenvironment, providing novel insights into tumour immunotherapy.

Keywords:  immunotherapy; metabolic disorder; tumour immunology

DOI:  https://doi.org/10.1111/imm.13444
Cell. 2021 Dec 18. pii: S0092-8674(21)01427-6. [Epub ahead of print]

EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion.

Antonio Marzio, Emma Kurz, Jennifer M Sahni, Giuseppe Di Feo, Joseph Puccini, Shaowen Jiang, Carolina Alcantara Hirsch, Arnaldo A Arbini, Warren L Wu, Harvey I Pass, Dafna Bar-Sagi, Thales Papagiannakopoulos, Michele Pagano.

  Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often resistant to immunotherapy. Here, we show that KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY, producing a BRCAness phenotype, i.e., HRR defects and sensitivity to PARP inhibitors. Defective HRR contributes to a high tumor mutational burden that, in turn, is expected to prompt an innate immune response. Notably, EMSY accumulation suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways, individually or in combination, represents a therapeutic strategy in NSCLC patients harboring alterations in KEAP1.

Keywords:  BRCAness; EMSY; KEAP1; NSCLC; PARP inhibitors; STING agonsts; immune evasion; interferon; lung cancer; ubiquitination

DOI:  https://doi.org/10.1016/j.cell.2021.12.005