The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction

Abstract

SUMMARYAlthough tumor-specific T cells recognize cancer cells, they are often rendered dysfunctional due to an immunosuppressive microenvironment. Here we showed that T cells demonstrated persistent loss of mitochondrial function and mass when infiltrating murine and human tumors, an effect specific to the tumor microenvironment and not merely caused by activation. Tumor-infiltrating T cells showed a progressive loss of PPAR-gamma coactivator 1α (PGC1α), which programs mitochondrial biogenesis, induced by chronic Akt signaling in tumor-specific T cells. Reprogramming tumor-specific T cells through enforced expression of PGC1α resulted in superior intratumoral metabolic and effector function. Our data support a model in which signals in the tumor microenvironment repress T cell oxidative metabolism, resulting in effector cells with metabolic needs that cannot be met. Our studies also suggest that modulation or reprogramming of the altered metabolism of tumor-infiltrating T cells might represent a potential strategy to reinvigorate dysfunctional T cells for cancer treatment. Abstract * Correspondence: gdelgoffe@pitt.edu.

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

“…(iv) Finally, PGC-1α and its cofactors, NRFs and PPARs, induce a series of transcription factors, which activate fatty acid oxidation and OXPHOS, and mitochondrial expansion, which promotes CTL activation and proliferation. Two papers very recently published, showing that PD-1 signal blocks mitochondrial activity and PGC-1α expression, strongly support our hypothesis (55,56). Together, all chemicals used in this study-namely ROS, uncouplers, AMPK activators, mTOR activators, and PGC-1α activators-lead to CD8 + T-cell activation and differentiation through mitochondrial activation and expansion when combined with PD-1 blockade but not by the chemicals alone.…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Additionally, TME can deeply affect the metabolic balance of T EX cells. Indeed, expression levels of the inhibitory receptors PD-1 and LAG-3 in TILs correlate with decreased mitochondrial mass and glucose uptake [207]. Given the importance of glucose availability to sustain T E glycolysis and effector functions [201], it becomes obvious that the glucose-limiting environment found in a tumor mass severely affects the anti-tumor immune response and cytokine production [208], thus favouring an imbalance towards T EX .…”

“…Consequently, in these conditions, mitochondrial mass and function are severely impaired and cytokine production is reduced. Indeed, forcing PCG1α expression in isolated TILs restores mitochondrial functionality and reduces tumor growth during ACI [207]. Considering the tight connection existing between mitochondrial metabolism and the shape of the mitochondrial network (see [209] for a review), we could expect an involvement of mitochondrial dynamics in TILs metabolism inside the tumor mass.…”

“…Considering the tight connection existing between mitochondrial metabolism and the shape of the mitochondrial network (see [209] for a review), we could expect an involvement of mitochondrial dynamics in TILs metabolism inside the tumor mass. Of note, it is still unknown whether or not differentiation to an exhausted phenotype in TILs could also affect mitochondrial dynamics, in addition to its well-established role on T EX mitochondrial metabolism [207,210]. Recently, by a microarray analysis in chronic viral-infected patients fit has been found that exhausted CD8+ T cells show significant downregulation in the expression of several genes associated with mitochondrial OXPHOS metabolism, and upregulation of the oxidative stress pathway.…”

Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma

“…Tumor cell production of lactic acid can also suppress T cell signaling through NFAT and IFN-γ secretion to impair antitumor immunity (11). Tumor infiltrating lymphocytes (TIL) have been reported to lose mitochondrial mass in a melanoma model, rendering T cells unable to efficiently meet bioenergetic needs (26). While restoring T cell glucose uptake and glycolytic intermediates (24,27) or mitochondrial mass (26) can improve TIL function, the mechanisms and role of T cell metabolic inhibition in cancer remain poorly understood.…”