Self-Maintaining CD103⁺ Cancer-Specific T Cells Are Highly Energetic with Rapid Cytotoxic and Effector Responses

Enrichment of CD103⁺ tumor-infiltrating T lymphocytes (TIL) is associated with improved outcomes in patients. However, the characteristics of human CD103⁺ cytotoxic CD8⁺ T cells (CTL) and their role in tumor control remain unclear. We investigated the features and antitumor mechanisms of CD103⁺ CTLs by assessing T-cell receptor (TCR)-matched CD103⁺ and CD103^- cancer-specific CTL immunity in vitro and its immunophenotype ex vivo Interestingly, we found that differentiated CD103⁺ cancer-specific CTLs expressed the active form of TGFβ1 to continually self-regulate CD103 expression, without relying on external TGFβ1-producing cells. The presence of CD103 on CTLs improved TCR antigen sensitivity, which enabled faster cancer recognition and rapid antitumor cytotoxicity. These CD103⁺ CTLs had elevated energetic potential and faster migration capacity. However, they had increased inhibitory receptor coexpression and elevated T-cell apoptosis following prolonged cancer exposure. Our data provide fundamental insights into the properties of matured human CD103⁺ cancer-specific CTLs, which could have important implications for future designs of tissue-localized cancer immunotherapy strategies.