It has now become clear that the immune system is not oblivious to cancer initiation and progression, but rather is rendered dysfunctional through a wide array of tolerogenic mechanisms. One of these is the generation of a potently immunosuppressive microenvironment, characterized by altered populations of suppressive cells, secretion of suppressive cytokines, and upregulation of inhibitory ligands. The tumor microenvironment also possesses, due to the deregulated energetics of cancer cells, an altered metabolic profile: hypoxia, acidosis, and a dearth of glucose and other carbon sources. T cell activation and effector function are metabolically demanding, requiring elevated glucose processing and mitochondrial activity to keep up with the bioenergetic demands of proliferation, cytokine secretion, and cytolytic capacity. Thus, we sought to determine whether the metabolism of the tumor microenvironment acts as a barrier to antitumor immunity and resistance mechanism to immunotherapy. We have demonstrated that T cells infiltrating murine and human tumors exhibit a phenotype of metabolic insufficiency, characterized by decreased glucose uptake and a crippling loss of mitochondrial function. We show that this loss of oxidative function is specific to the chronic activation observed in the tumor microenvironment, and occurs rapidly upon entry into the tumor. This loss of mitochondrial activity and mass is due, in part, to the repression of PGC1α, a transcriptional co-activator that programs mitochondrial biogenesis. Further, we have identified chronic Akt activation and consequent Foxo inactivation as a major driver of PGC1α repression. Importantly, metabolic reprogramming of tumor-specific T cells to enforce mitochondrial biogenesis results in dramatically increased antitumor immunity, characterized by robust proliferation, cytokine production, and tumor regression and clearance. Our data support a model in which mitochondrial insufficiency represents a primordial checkpoint inhibiting antitumor immunity in addition to immunologic suppression. Further supporting this notion are additional studies from our laboratory suggesting that selective boosting of T cell mitochondrial activity through mitigation of tumor hypoxia dramatically enhances immunotherapies like checkpoint blockade and adoptive cell therapy. Our data suggest not only that the metabolic nature of the tumor microenvironment may be predictive of a patient's response to various immunotherapies, but that metabolic reprogramming of T cells or the microenvironment itself may be an important means to improve the immunotherapeutic treatment of cancer.

Citation Format: Greg M. Delgoffe. Identifying and overcoming metabolic checkpoints to antitumor immunity [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA08.