Antigen reactivity defines tissue-resident memory and exhausted T cells in tumors

CD8⁺ T cells are an important weapon in the therapeutic armamentarium against cancer. While CD8⁺CD103⁺ T cells with a tissue-resident memory T (T_RM) cell phenotype are associated with favorable prognoses, the tumor microenvironment also contains dysfunctional exhausted T (T_EX) cells that exhibit a variety of T_RM-like features. Here we deconvolute T_RM and T_EX cells across human cancers, ascribing markers and gene signatures that distinguish these populations and enable their functional distinction. Although T_RM cells have superior functionality and are associated with long-term survival post-tumor resection, they are not associated with responsiveness to immune checkpoint blockade. Tumor-associated T_EX and T_RM cells are clonally distinct, with the latter comprising tumor-independent bystanders and tumor-specific cells segregated from cognate antigen. Intratumoral T_RM cells can be forced toward an exhausted fate when chronic antigen stimulation occurs, indicating that the presence or absence of continuous antigen exposure within the microenvironment is the key distinction between tumor-associated T_EX and T_RM populations. These results highlight unique functions for T_RM and T_EX cells in tumor control, underscoring the need for distinct strategies to harness these populations for cancer therapies.