Tumor secreted extracellular vesicles regulate T-cell costimulation and can be manipulated to induce tumor specific T-cell responses

Abstract

SUMMARYTumor intrinsic factors negatively regulate tumor immune cell infiltration and function. Deciphering the underlying mechanisms is critical to improving immunotherapy in cancers. Our analyses of human colorectal cancer (CRC) immune profiles and tumor-immune cell interactions revealed that tumor cell secreted extracellular vesicles (TEVs) induced immunosuppression in CRC. Specifically, TEVs containing microRNA miR-424 suppressed the CD28-CD80/86 costimulatory pathway in tumor infiltrating T cells and dendritic cells. Modified TEVs with miR-424 knocked down enhanced T-cell mediated antitumor immune response in CRC tumor models and increased the response to immune checkpoint blockade therapies (ICBT). Intravenous injections of modified TEVs induced tumor antigen specific immune responses. Moreover, injections of modified TEVs boosted the ICBT efficacy in CRC models that mimic treatment refractory late-stage disease. Collectively, we demonstrate a critical role for TEVs in antitumor immune regulation and immunotherapy response, which could be developed as a novel treatment for ICBT resistant human CRC.