1. Tumor-Secreted Extracellular Vesicles Regulate T-Cell Costimulation and Can Be Manipulated To Induce Tumor-Specific T-Cell Responses.
- Author
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Zhao X, Yuan C, Wangmo D, and Subramanian S
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, B7-1 Antigen genetics, B7-1 Antigen metabolism, B7-2 Antigen genetics, B7-2 Antigen metabolism, CD28 Antigens genetics, CD28 Antigens metabolism, Caco-2 Cells, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Dendritic Cells immunology, Dendritic Cells metabolism, Drug Resistance, Neoplasm, Extracellular Vesicles drug effects, Extracellular Vesicles genetics, Extracellular Vesicles metabolism, HT29 Cells, Humans, Immune Checkpoint Inhibitors pharmacology, Jurkat Cells, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, MicroRNAs genetics, MicroRNAs metabolism, Phenotype, Tumor Hypoxia, Colorectal Neoplasms immunology, Extracellular Vesicles immunology, Lymphocyte Activation, Lymphocytes, Tumor-Infiltrating immunology, Tumor Microenvironment
- Abstract
Background & Aims: 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 patients with colorectal cancer (>85%) have microsatellite stable tumors that do not respond. In this study, we aimed to decipher the underlying tumor-intrinsic mechanisms critical for improving immunotherapy in colorectal cancer., Methods: 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 antitumor immune response., Results: Our analyses of human colorectal cancer immune profiles and tumor-immune cell interactions showed that tumor-secreted EVs containing microRNA miR-424 suppressed the CD28-CD80/86 costimulatory 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 antitumor 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., Conclusions: Collectively, we show a critical role for tumor-secreted EVs in antitumor immune regulation and immunotherapy response, which could be developed as a novel treatment for immune checkpoint blockade-resistant colorectal cancer., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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