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Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression.

ABSTRACT: Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that glucose consumption by tumors metabolically restricts T cells, leading to their dampened mTOR activity, glycolytic capacity, and IFN-? production, thereby allowing tumor progression. We show that enhancing glycolysis in an antigenic "regressor" tumor is sufficient to override the protective ability of T cells to control tumor growth. We also show that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, which are used clinically, restore glucose in tumor microenvironment, permitting T cell glycolysis and IFN-? production. Furthermore, we found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of glycolysis enzymes, reflecting a role for PD-L1 in tumor glucose utilization. Our results establish that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer.

SUBMITTER: Chang CH

PROVIDER: S-EPMC4864363 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression.

Chang Chih-Hao CH Qiu Jing J O'Sullivan David D Buck Michael D MD Noguchi Takuro T Curtis Jonathan D JD Chen Qiongyu Q Gindin Mariel M Gubin Matthew M MM van der Windt Gerritje J W GJ Tonc Elena E Schreiber Robert D RD Pearce Edward J EJ Pearce Erika L EL

Cell 20150827 6

Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that glucose consumption by tumors metabolically restricts T cells, leading to their dampened mTOR activity, glycolytic capacity, and IFN-γ production, thereby allowing tumor progression. We show that enhancing glycolysis in an antigenic "regressor" tumor is sufficient to override the protective ability of ...[more]

PMID: 26321679

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Project description:Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME, the immune checkpoints and immunosuppressive chemokines, and currently used inhibitors targeting these pathways. These include both intrinsic and non-autonomous tumor cell signaling pathways in the TME: protein kinase C (PKC) signaling, Notch, and transforming growth factor (TGF-β) signaling, Endoplasmic Reticulum (ER) stress response, lactate signaling, Metabolic reprogramming, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and Siglec signaling pathways. We also discuss the recent advances in Programmed Cell Death Protein 1 (PD-1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), T-cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte Activating Gene 3 (LAG3) immune checkpoint inhibitors along with the C-C chemokine receptor 4 (CCR4)- C-C class chemokines 22 (CCL22)/ and 17 (CCL17), C-C chemokine receptor type 2 (CCR2)- chemokine (C-C motif) ligand 2 (CCL2), C-C chemokine receptor type 5 (CCR5)- chemokine (C-C motif) ligand 3 (CCL3) chemokine signaling axis in the TME. In addition, this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME, which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer therapies. We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response. Overall, this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME, highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology. We highlight the importance of the most recent technologies of microfluidics and lab-on-chip models for TME research and also present an overview of extrinsic factors, such as the inhabitant human microbiome, which have the potential to modulate TME biology and drug responses.

Project description:High-dose dexamethasone (DEX) is used to treat chemotherapy-induced nausea and vomiting or to control immunotherapy-related autoimmune diseases in clinical practice. However, the underlying mechanisms of high-dose DEX in tumor progression remain unaddressed. Therefore, we explored the effects of high-dose DEX on tumor progression and the potential mechanisms of its anti-tumor function using immunohistochemistry, histological examination, real-time quantitative PCR (qPCR), and Western blotting. Tumor volume, blood vessel invasion, and levels of the cell proliferation markers Ki67 and c-Myc and the anti-apoptotic marker Bcl2 decreased in response to high-dose DEX. However, the cell apoptosis marker cleaved caspase 3 increased significantly in mice treated with 50 mg/kg DEX compared with controls. Some genes associated with immune responses were significantly downregulated following treatment with 50 mg/kg DEX e.g., Cxcl9, Cxcl10, Cd3e, Gzmb, Ifng, Foxp3, S100a9, Arg1, and Mrc1. In contrast, the M1-like tumor-associated macrophages (TAMs) activation marker Nos2 was shown to be increased. Moreover, the expression of peroxisome proliferator-activated receptors ? and ? (Ppar? and Pparg, respectively) was shown to be significantly upregulated in livers or tumors treated with DEX. However, high-dose DEX treatment decreased the expression of glucose and lipid metabolic pathway-related genes such as glycolysis-associated genes (Glut1, Hk2, Pgk1, Idh3a), triglyceride (TG) synthesis genes (Gpam, Agpat2, Dgat1), exogenous free fatty acid (FFA) uptake-related genes (Fabp1, Slc27a4, and CD36), and fatty acid oxidation (FAO) genes (Acadm, Acaa1, Cpt1a, Pnpla2). In addition, increased serum glucose and decreased serum TG and non-esterified fatty acid (NEFA) were observed in DEX treated-xenografted tumor mice. These findings indicate that high-dose DEX-inhibited tumor progression is a complicated process, not only activated by M1-like TAMs, but also decreased by the uptake and consumption of glucose and lipids that block the raw material and energy supply of cancer cells. Activated M1-like TAMs and inefficient glucose and lipid metabolism delayed tumor cell growth and promoted apoptosis. These findings have important implications for the application of DEX combined with drugs that target key metabolism pathways for tumor therapy in clinical practice.

Project description:BackgroundThe existence of immunologically 'cold tumors' frequently found across a wide spectrum of tumor types represents a significant challenge for cancer immunotherapy. Cold tumors have poor baseline pan-leukocyte infiltration, including a low prevalence of cytotoxic lymphocytes, and not surprisingly respond unfavorably to immune checkpoint (IC) inhibitors. We hypothesized that cold tumors harbor a mechanism of immune escape upstream and independent of ICs that may be driven by tumor biology rather than differences in mutational neoantigen burden.MethodsUsing a bioinformatic approach to analyze TCGA (The Cancer Genome Atlas) RNA sequencing data we identified genes upregulated in cold versus hot tumors across four different smoking-related cancers, including squamous carcinomas from the oral cavity (OCSCC) and lung (LUSC), and adenocarcinomas of the bladder (BLCA) and lung (LUAD). Biological significance of the gene most robustly associated with a cold tumor phenotype across all four tumor types, glutathione peroxidase 2 (GPX2), was further evaluated using a combination of in silico analyses and functional genomic experiments performed both in vitro and in in vivo with preclinical models of oral cancer.ResultsElevated RNA expression of five metabolic enzymes including GPX2, aldo-keto reductase family 1 members AKR1C1, AKR1C3, and cytochrome monoxygenases (CP4F11 and CYP4F3) co-occurred in cold tumors across all four smoking-related cancers. These genes have all been linked to negative regulation of arachidonic acid metabolism-a well-established inflammatory pathway-and are also known downstream targets of the redox sensitive Nrf2 transcription factor pathway. In OCSCC, LUSC, and LUAD, GPX2 expression was highly correlated with Nrf2 activation signatures, also elevated in cold tumors. In BLCA, however, GPX2 correlated more strongly than Nrf2 signatures with decreased infiltration of multiple leukocyte subtypes. GPX2 inversely correlated with expression of multiple pro- inflammatory cytokines/chemokines and NF-kB activation in cell lines and knockdown of GPX2 led to increased secretion of prostaglandin E2 (PGE2) and interleukin-6. Conversely, GPX2 overexpression led to reduced PGE2 production in a murine OCSCC model (MOC1). GPX2 overexpressing MOC1 tumors had a more suppressive tumor immune microenvironment and responded less favorably to anti-cytotoxic T-lymphocytes-associated protein 4 IC therapy in mice.ConclusionGPX2 overexpression represents a novel potentially targetable effector of immune escape in cold tumors.

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Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression.

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Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression.

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