T cell exhaustion is a major contributor to immunosuppression in the tumor microenvironment (TME). Blockade of key regulators of T cell exhaustion, such as PD-1, can reinvigorate
tumor-specific T cells and activate anti-
tumor immunity in various types of
cancer. Here, 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 anti-
tumor immunity both in vitro and in vivo, and loss of CD106 in CD8+ T cells suppressed
tumor growth and improved response to PD-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.