Tumor-Secreted Extracellular Vesicles Regulate T-Cell Costimulation and Can Be Manipulated To Induce Tumor-Specific T-Cell Responses

Xianda Zhao, Ce Yuan, Dechen Wangmo, Subbaya Subramanian

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)560-574.e11
JournalGastroenterology
Volume161
Issue number2
DOIs
StatePublished - Aug 2021

Bibliographical note

Funding Information:
Funding This work is supported by the Minnesota Colorectal Cancer Research Foundation, Mezin-Koats Colon Cancer Research Award, Department of Surgery Research Fund, and Clinical and Translational Science Institute at the University of Minnesota.

Publisher Copyright:
© 2021 AGA Institute

Keywords

  • CD28
  • CD80
  • Colorectal Cancer
  • Extracellular Vesicles
  • T-Cell Costimulation

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