Chronic antigen in solid tumors drives a distinct program of T cell residence

Analyses of healthy tissue reveal signatures that identify resident memory CD8⁺ T cells (T_RM), which survey tissues without recirculating. The density of T_RM phenotype cells within solid tumors correlates favorably with prognosis, suggesting that intratumoral residents control cancer. However, residence has not been directly tested, and intratumoral T_RM phenotype cells could instead reflect aspects of the microenvironment that correlate with prognosis. Using a breast cancer model in mice, we found that conventional T_RM markers do not inform the tumor residence of either bystander or tumor-specific cells, which exhibit further distinct phenotypes in the tumor microenvironment and healthy mammary tissue. Rather, tumor-specific, stem progenitor CD8⁺ T cells migrate to tumors and become resident while acquiring select markers of exhaustion. These data indicate that tonic antigen stimulation and the tumor environment drive distinct programs of residence compared with healthy tissues and that tumor immunity is sustained by continued migration of tumor-specific stem cells.