Abstract
Breakthroughs in anti-tumor immunity have led to unprecedented advances in immunotherapy, yet it is now clear that the tumor microenvironment (TME) restrains immunity. T cells must substantially increase nutrient uptake to mount a proper immune response and failure to obtain sufficient nutrients or engage the appropriate metabolic pathways can alter or prevent effector T cell differentiation and function. The TME, however, can be metabolically hostile due to insufficient vascular exchange and cancer cell metabolism that leads to hypoxia, depletion of nutrients, and accumulation of waste products. Further, inhibitory receptors present in the TME can inhibit T cell metabolism and alter T cell signaling both directly and through release of extracellular vesicles such as exosomes. This review will discuss the metabolic changes that drive T cells into different stages of their development and how the TME imposes barriers to the metabolism and activity of tumor infiltrating lymphocytes.
Highlights
Hanahan and Weinberg’s seminal paper ‘The Hallmarks of Cancer’ was revised in 2011 to include deregulating cellular energetics and evasion of immune destruction (Hanahan and Weinberg, 2011)
A similar metabolic shift and decrease in cytokine production was observed upon PD-1 ligation activating STAT3 in CD8+ T cells, facilitating obesity-associated breast cancer progression (Zhang et al, 2020). These findings suggest that PD-1 blockade may function synergistically at two levels by re-invigorating T cell glycolysis while simultaneously inhibiting tumor cell glycolysis
Disruption of T cell activation due to altered tumor cell metabolism and other metabolic features in the tumor microenvironment (TME) indicates that this is an important mechanism for immunosuppression
Summary
Hanahan and Weinberg’s seminal paper ‘The Hallmarks of Cancer’ was revised in 2011 to include deregulating cellular energetics and evasion of immune destruction (Hanahan and Weinberg, 2011). Treating human ovarian cancer-specific T cells with an EZH2 inhibitor prior to adoptive transfer led to increased tumor growth in a humanized ovarian cancer mouse model (Zhao et al, 2016) These data suggest that glucose metabolism can regulate T cell polyfunctionality by modulating EZH2 expression, whether one should induce EZH2 expression in cancer patients is complicated since some cancers acquire gain-of-function mutations in this methyltransferase (Kim and Roberts, 2016). Adding bicarbonate to neutralize acidic environments improved response rates to checkpoint inhibition and adoptive cell therapy in mice models of melanoma (Pilon-Thomas et al, 2016) Taken together, these studies indicate that finetuning T cell metabolism in vitro prior to transfusion back into patients is key to their success in vivo
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