IL-12 alters T-cell metabolism to augment anti-tumor immunotherapy

Abstract To better limit tumor growth, adoptive T cell therapy (ACT), a cutting-edge new strategy for treating cancer, permits patients’ T cells to be modified. Long-lived central memory cells (Tcm), a specific subset of T cells, have been demonstrated through studies conducted in our group and others to be more effective at controlling tumor burden. Powerful inflammatory cytokine IL-12 has been extensively studied for its roles in the interaction of innate and adaptive immunity; however, therapeutic potential has not been optimized. We hypothesized that ex vivo administration of IL-12 may improve metabolic fitness and anti-tumor capabilities of T cells. Using a B16 murine melanoma model and T cells that are reactive to the melanoma epitope gp100, we found ex-vivo conditioning with IL-12 increased stem cell memory (Tscm) and central memory (Tcm) T cell populations. Additionally, we found unique metabolic signatures and proliferation patterns were dependent on IL-12 duration. We also observed enhanced engraftment and tumor control for up to 60 days after adoptively transferring these cells into animals with subcutaneous melanoma tumors. These metabolically conditioned T cells showed improved mitochondrial mass and function, elevated cytokine output, and perforin expression. Aside from switching from glycolysis to oxidative phosphorylation, these cells were also able to continue producing cytokines even when glucose or pyruvate levels dropped. Together, these findings imply that IL-12 modifies T cells’ reliance on glucose for energy while preserving their anti-tumor ability, potentially amplifying their ability to fight tumors in nutrient deprived microenvironments. IL-12 could therefore have a large impact on future ACT strategies. R01 CA250458, R01 CA236379