CD49a targeting enhances NK cell function and antitumor immunity

Abstract Approximately 70% of patients receiving immune checkpoint blockade therapies develop treatment resistance. Thus, there is a need for the identification of additional immunotherapeutic targets. CD49a is a membrane protein expressed on NK cells and T cells. In this study, we found that CD49a was highly expressed on the surface of tumor-infiltrating NK cells in various mouse tumor models, and that CD49a+ tumor-infiltrating NK cells were more exhausted than CD49a- tumor-infiltrating NK cells. Furthermore, CD49a or NK-specific CD49a deficiency slowed tumor growth and prolonged survival in several mouse tumor models, primarily through the essential role played by NK cells in antitumor activities. Blockade of CD49a using a monoclonal antibody suppressed tumor development in mice and combination treatment with anti-PD-L1 further enhanced antitumor efficacy. Our research reveals CD49a on NK cells as an immunotherapeutic target, and highlights the potential clinical applications of CD49a-targeted therapies.