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

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Colorectal Cancer is a major cause of cancer-related deaths worldwide. Immune checkpoint blockade therapies are effective in 30-60% of the microsatellite instable-high subtype. Unfortunately, most colorectal cancer patients (>85%) have microsatellite stable tumors, that do not respond. In this study, we aim to decipher the underlying tumor intrinsic mechanisms critical for improving immunotherapy in colorectal cancer.We used human and mouse tumor samples, cell lines, human colorectal cancer organoids, and various syngeneic orthotopic mouse models of late-stage colorectal cancer to define the effects of tumor cell-secreted extracellular vesicles (EVs) on anti-tumor immune response.Our analyses of human colorectal cancer immune profiles and tumor-immune cell interactions revealed that tumor secreted EVs containing microRNA miR-424 suppressed the CD28-CD80/86 co-stimulatory pathway in tumor-infiltrating T cells and dendritic cells, leading to immune checkpoint blockade resistance. Modified tumor secreted EVs with miR-424 knocked down enhanced T-cell mediated anti-tumor immune response in colorectal cancer tumor models and increased the immune checkpoint blockade response. Intravenous injections of modified tumor secreted EVs induced tumor antigen-specific immune responses and boosted the immune checkpoint blockade efficacy in colorectal cancer models that mimic aggressively progressing late-stage disease.Collectively, we demonstrate a critical role for tumor secreted extracellular vesicles in anti-tumor immune regulation and immunotherapy response, which could be developed as a novel treatment for immune checkpoint blockade resistant colorectal cancer.

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Authors: Xianda Zhao, Ce Yuan, Dechen Wangmo, Subbaya Subramanian