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. 2018 Aug 13;8:284.
doi: 10.3389/fonc.2018.00284. eCollection 2018.

Metabolic Switch in the Tumor Microenvironment Determines Immune Responses to Anti-cancer Therapy

Free PMC article

Metabolic Switch in the Tumor Microenvironment Determines Immune Responses to Anti-cancer Therapy

Barbara Wegiel et al. Front Oncol. .
Free PMC article


Tumor-induced immune tolerance permits growth and spread of malignant cells. Cancer cells have strong influence on surrounding cells and shape the hypoxic tumor microenvironment (TME) facilitating cancer progression. A dynamic change in glucose metabolism occurring in cancer cells and its influence on the TME are still poorly understood. Indeed, cancer and/or immune cells undergo rapid adaptation in metabolic pathways during cancer progression. Metabolic reprograming affects macrophages, T cells, and myeloid derived suppressor cells (MDSCs) among other immune cells. Their role in the TME depends on a nature and concentration of factors, such as cytokines, reactive oxygen species (ROS), growth factors, and most importantly, diffusible metabolites (i.e., lactate). Further, the amounts of available nutrients and oxygen as well as activity of microbiota may influence metabolic pathways in the TME. The roles of metabolites in regulating of the interaction between immune and cancer cell are highlighted in this review. Targeting metabolic reprogramming or signaling pathways controlling cell metabolism in the TME might be a potential strategy for anti-cancer therapy alone or in combination with current immunotherapies.

Keywords: HIF-1α; immune stroma; lactate; metabolic reprogramming; tumor microenvironment (TME).


Figure 1
Figure 1
Cell fate in the hypoxic TME. Low oxygen levels, typical of the poorly vascularized tumor milieu, can affect both tumor and immune cells through the stabilization of HIF-1α. It directly promotes tumor growth through the upregulation of genes involved in glycolysis, LDH-A. HIF-1α up-regulation drives expression of PDL-1 and Arg-1 that potentiate the immune suppressive TME. Hypoxia-induced HIF1α and LDH-A-derived lactate strongly modulates the TME. Lactate acts directly on the cells or through the pH changes in the niche. The most notable effects are: (i) polarization of TAM into M2 macrophages; (ii) accumulation of myeloid-derived suppressor cells (MDSCs) and T regs; (iii) inhibition of T effector cells.
Figure 2
Figure 2
Signaling pathways in the hypoxic TME. HIF-1α is a major regulator of hypoxia-responsive genes in the TME. Multiple signaling pathways crosstalk with or activate HIF-1α. AMPK activation in the TME drives cell catabolism and is important for HIF-1α-regulated transcription. AMPK allows for metabolic adaptation in hypoxia with low ATP and lack of nutrient. Hypoxia also induces PI3K signaling through Akt-mTOR that promotes anti-apoptotic responses and metabolic shift toward glycolysis.

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    1. Krstic J, Trivanovic D, Jaukovic A, Santibanez JF, Bugarski D. Metabolic plasticity of stem cells and macrophages in cancer. Front Immunol. (2017) 8:939. 10.3389/fimmu.2017.00939 - DOI - PMC - PubMed
    1. Lyssiotis CA, Kimmelman AC. Metabolic interactions in the tumor microenvironment. Trends Cell Biol. (2017) 27:863–75. 10.1016/j.tcb.2017.06.003 - DOI - PMC - PubMed
    1. Norata GD, Caligiuri G, Chavakis T, Matarese G, Netea MG, Nicoletti A, et al. . The cellular and molecular basis of translational immunometabolism. Immunity (2015) 43:421–34. 10.1016/j.immuni.2015.08.023 - DOI - PubMed
    1. Chang CH, Pearce EL. Emerging concepts of T cell metabolism as a target of immunotherapy. Nat Immunol. (2016) 17:364–8. 10.1038/ni.3415 - DOI - PMC - PubMed
    1. Molon B, Cali B, Viola A. T cells and cancer: how metabolism shapes immunity. Front Immunol. (2016) 7:20. 10.3389/fimmu.2016.00020 - DOI - PMC - PubMed

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