Editors' ChoiceCancer

Re-energizing exhausted T cells?

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Science Translational Medicine  24 Aug 2016:
Vol. 8, Issue 353, pp. 353ec135
DOI: 10.1126/scitranslmed.aah5499

CD8+ T cells exist in distinct, functional states that exhibit unique energetic requirements. Whereas naïve T cells are largely quiescent, in the effector phase T cells must rapidly divide, replicate their DNA, synthesize cytokines, and mobilize to deliver their payload to target cells. Importantly, in the context of the tumor microenvironment, where hypovascularization results in nutrient depletion, the inability of T cells to adapt to changing nutrient availability may impair local function, persistence, and survival. In this work, Scharping et al. test the hypothesis that T cell dysfunction within the tumor microenvironment is linked to cell-intrinsic metabolic deficiencies and that reprogramming infiltrating T cells could increase antitumor activity.

Using an injectable model of murine melanoma, the authors discovered that tumor infiltrating CD8+ T cells, both bulk and tumor-specific, demonstrate decreased mitochondrial mass and function when compared with lymph node lymphocytes. Impaired mitochondrial biogenesis was not a function of activation, as acute viral infection did not recapitulate the metabolic phenotype. The specificity to the nutrient-poor, immunosuppressive tumor microenvironment suggested local reprogramming. Interestingly, while decreased mitochondrial mass inversely correlated with immune checkpoint expression, cytokine production, and T cell exhaustion, repression of oxidative metabolism was T cell–intrinsic and not influenced by immune checkpoint blockade targeting or depletion of regulatory T cells. Rather, progressive loss of peroxisome proliferator–activated receptor-γ coactivator 1α (PGC1α), a regulator of mitochondrial replication, was observed in the context of sustained Akt signaling likely driven by chronic antigen exposure in the tumor microenvironment. Importantly, enforced expression of PGC1α in T cells rescued effector function and enhanced efficacy of adoptive cell therapy, indicating that persistent mitochondrial function is linked to cytotoxic T cell activity in vivo.

Loss of mitochondrial mass was also observed in T cells infiltrating human head and neck squamous cell carcinomas as compared with peripheral blood indicating that metabolism as a mechanism of local T cell exhaustion might apply clinically. The data presented here indicates that T cell reinvigoration, achieved through checkpoint blockade, may be incomplete in the presence of severe metabolic insufficiency, and consequently metabolic reprogramming may synergize with immunotherapy to boost intratumoral efficacy of tumor-specific T cells.

N. E. Scharping et al., The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45, 374–388 (2016). [Abstract]

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