A small but mighty ROR(γt): RORγt supports peripherally induced regulatory T-cell function and tumor growth 4146

Abstract Description Despite recent advances in immunotherapy, cancer continues to be the second leading cause of death in the United States. The presence of regulatory T-cells (Tregs) in tumors is often correlated with poor prognosis. Treg-targeted therapies show anti-tumor efficacy, but many patients experience immune-related adverse events due to the loss of systemic tolerance. RORγt+ peripherally induced regulatory T-cells (pTregs) are a microbially-driven population of Tregs in the gut that have independent functions from thymic Tregs; however, unique targetable mechanisms utilized by pTregs to promote tumor growth are unknown. We hypothesize that RORγt stabilizes the suppressive function of pTregs to promote tumor growth both indirectly (by altering the microbiome composition) and directly (by inhibiting effector T cells). Utilizing Foxp3CreERT2Rorcfl/fl mice, we have found that RORγt expression stabilizes Foxp3 expression and increases suppressive function in pTregs that ultimately promotes tumor growth. Tumors isolated from Foxp3CreERT2Rorcfl/fl mice have increased tumor infiltrating lymphocytes, including Th17 T cells and polyfunctional CD8+ T cells. Interestingly, we have found that this effect is dependent upon the gut microbiome, suggesting that pTregs support tumor growth through modification of the microbiota. Overall, we have found that pTregs drive tumor growth through the gut microbiota and represent a novel cellular target for immunotherapy development. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)