Differentiation of Cytotoxic CD8⁺ T Cell Subsets Under Tumor Progression: Can CD69 Be a New Therapeutic Target?

Tumor-specific CD8⁺ T cells play a pivotal role in anti-tumor immunity. Here, we review the heterogeneity of CD8⁺ T cell subsets during tumor progression. While both acute and chronic viral infections induce distinct CD8⁺ T cell responses, chronic responses are also observed during tumor development. Chronic immune responses have traditionally been considered to represent a dysfunctional state of CD8⁺ T cells, whereas the identification of TCF1⁺ stem-like CD8⁺ T cells has highlighted their importance in anti-tumor immunity. During tumor progression, TCF1⁺ stem-like CD8⁺ T cells differentiate into cytotoxic Tim-3⁺ terminally differentiated CD8⁺ T cells through mechanisms that remain largely unknown. We recently identified CD69 as an important regulator of chronic CD8⁺ T cell responses and showed that blocking CD69 function, either through the administration of anti-CD69 antibody (Ab) or genetic knockout, enhanced the generation of cytotoxic Tim-3⁺ terminally differentiated CD8⁺ T cells in both tumor-draining lymph nodes (TDLNs) and the tumor microenvironment (TME), thereby enhancing the anti-tumor immune response. These findings suggest that CD69 is an attractive therapeutic target that controls the chronic anti-tumor CD8⁺ T cell response.