Funding
Japan Society for the Promotion of Science (JSPS)
Japan Agency for Medical Research and Development (AMED)
Japan Science and Technology Agency (JST)
Naito Foundation (内藤記念科学振興財団)
Mitsubishi Foundation (The Mitsubishi Foundation)
Astellas Foundation for Research on Metabolic Disorders
Princess Takamatsu Cancer Research Fund
Pharmacology Research Foundation
Canon Foundation
KOTAI Biotechnologies Inc
Uehara Memorial Foundation (UMF)
Chugai Foundation for Innovative Drug Discovery Science
Kato Memorial Bioscience Foundation
ARTICLE ABSTRACT
T-cell exhaustion is a major contributor to immunosuppression in the tumor microenvironment (TME). Blockade of key regulators of T-cell exhaustion, such as programmed death 1, can reinvigorate tumor-specific T cells and activate antitumor immunity in various types of cancer. In this study, we identified that CD106 was specifically expressed in exhausted CD8+ T cells in the TME using single-cell RNA sequencing. High CD106 expression in the TME in clinical samples corresponded to improved response to cancer immunotherapy. CD106 in tumor-specific T cells suppressed antitumor immunity both in vitro and in vivo, and loss of CD106 in CD8+ T cells suppressed tumor growth and improved response to programmed death 1 blockade. Mechanistically, CD106 inhibited T-cell receptor (TCR) signaling by interacting with the TCR/CD3 complex and reducing its surface expression. Together, these findings provide insights into the immunosuppressive role of CD106 expressed in tumor-specific exhausted CD8+ T cells, identifying it as a potential biomarker and therapeutic target for cancer immunotherapy.Significance: CD106 is specifically expressed in tumor-specific exhausted CD8+ T cells and inhibits the TCR signaling pathway by reducing surface expression of the TCR/CD3 complex to suppress antitumor immunity.
