Fatty-Acid Catabolism Promotes T-cell Revitalization in Melanoma

Concurrent depletion of glucose and oxygen in the tumor microenvironment is driven by enhanced glucose consumption by tumor cells combined with lack of angiogenesis. It is unclear how CD8⁺ tumor-infiltrating lymphocytes (TIL), which preferentially use glycolysis (or oxidative phosphorylation if glucose levels are low), can metabolically adapt to a hypoglycemic and hypoxic tumor microenvironment and maintain growth and effector functions. Zhang and colleagues evaluated CD8⁺ TIL metabolism and functions during tumor progression in a transplantable mouse model of melanoma. Independent of antigen specificity, CD8⁺ TILs became increasingly metabolically stressed, entered a dysfunctional state known as exhaustion, and exhibited increased expression of HIF1α, the glucose transporter GLUT1, PD-1, and LAG3 during tumor progression. In tumor-bearing mice, activated TA-specific CD8⁺ TILs depleted of HIF1α delayed tumor progression and exhibited decreased LAG3 expression, no change in PD-1 expression, and enhanced effector function compared to CD8⁺ TILs with high HIF1α expression. HIF1α-depleted CD8⁺ TILs exhibited decreased expression of GLUT1 and increased expression of PPARα, which activates genes associated with fatty-acid (FA) catabolism and uptake. Normoxia and hypoglycemia induced CD8⁺ TIL dysfunction and short-term hypoxia induced decreased glycolysis and increased FA catabolism in CD8⁺TILs stimulated under hypoglycemia and in TA-specific CD8⁺ TILs from late-stage tumors. Similarly, CD8⁺ TILs from patients with melanoma were enriched for memory CD8⁺ T-cell subsets and exhibited increased PD-1 expression and enhanced FA catabolism. Treatment with anti–PD-1 inhibited tumor progression in a PD-L1–dependent manner but had no effect on CD8⁺ TIL function or metabolism. In vivo, treatment with a PPARα agonist resulted in increased FA catabolism, PD-1 expression, and effector functions in CD8⁺ TILs and enhanced the efficacy of anti–PD-1 treatment. These results elucidate the role of tumor microenvironment–induced metabolic reprogramming in T cells to preserve their functions and suggest that enhancing FA catabolism may improve the efficacy of immunotherapy in patients with melanoma.

Zhang Y, Kurupati R, Liu L, Zhou XY, Zhang G, Hudaihed A, et al. Enhancing CD8⁺ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 2017;32:377–91.

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