Engineering T cells to resist and convert immunosuppressive tumor microenvironments

A major challenge in adoptive T-cell therapy for solid tumors is the harsh immunosuppressive tumor microenvironment. Soluble factors such as transforming growth factor beta (TGF-β) play key roles in tumor immune evasion. Here, we report methods by which CARs can be engineered to respond to soluble antigens, and describe a novel TGF-β binding chimeric antigen receptor that rewires the T-cell response to TGF-β, converting this potent immunosuppressive molecule into a stimulant. We additionally elucidate mechanistic details of how CARs can be triggered by soluble ligands, as well as methods by which the signaling strength and ligand sensitivity of such CARs can be tuned. Given the modular nature of the engineered receptor, this work informs future efforts to redirect T-cell responses to extracellular soluble molecules. Citation Format: ZeNan L. Chang, Michael H. Lorenzini, Yvonne Y. Chen. Engineering T cells to resist and convert immunosuppressive tumor microenvironments [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr IA08.