Immunosuppressive mechanisms of intratumoral regulatory T cells

PROJECT SUMMARY Immune-based cancer therapies have revolutionized the treatment of cancer. However, immunosuppression within tumors remains a major obstacle for their success. Regulatory T cells (Tregs), an immunosuppressive subset of CD4+ T cells, are heavily recruited to most tumors where they may suppress antitumor immune responses directly within tumors. Tregs may also impose immunosuppression directly in the lymph nodes draining the tumor (tdLN), limiting T cell priming events that generate robust and potent antitumor T cells. Where Tregs function, in the tumor, tdLN, or both, is of critical importance for Treg-targeting cancer therapies because disrupting Tregs systemically will be highly toxic, whereas selectively targeting intratumoral Tregs (IT-Tregs), if effective against cancer, would treat cancers without autoimmune toxicities. Our objective is to decipher whether blocking Treg function in tumors is sufficient for tumor control and to uncover the mechanisms of IT-Treg immunosuppression. We hypothesize that Tregs function directly within tumors to suppress antitumor immune responses by reducing the capacity of dendritic cells (DCs) to endocytose tumor antigen, thereby also reducing T cell priming in the tdLN. Here we propose to investigate this hypothesis by studying experimental and therapeutic methods of IT-Treg ablation, which appear to effectively control primary tumors as well as untreated metastases without inciting autoimmunity. In this proposal we will investigate the mechanism of Treg control of DC antigen uptake (Aim 1), how altered antigen uptake locally in tumors enhances systemic immunity to metastases (Aim 2), and test whether therapeutically translatable Treg-depleting antibodies delivered intratumorally can also increase DC antigen uptake and promote systemic immune control of metastatic cancer (Aim 3). Our findings will uncover new genetic targets to prevent Treg suppression of DC priming of antitumor T cells without autoimmune toxicity.