Intratumoral CD8⁺ T cells with a tissue-resident memory phenotype mediate local immunity and immune checkpoint...

CD8⁺ tumor-infiltrating lymphocytes with a tissue-resident memory T (T_RM) cell phenotype are associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, the relative contribution of CD8⁺ T_RM cells to anti-tumor immunity and immune checkpoint blockade efficacy in breast cancer remains unknown. Here, we show that intratumoral CD8⁺ T cells in murine mammary tumors transcriptionally resemble those from TNBC patients. Phenotypic and transcriptional studies established two intratumoral sub-populations: one more enriched in markers of terminal exhaustion (T_EX-like) and the other with a bona fide resident phenotype (T_RM-like). Treatment with anti-PD-1 and anti-CTLA-4 therapy resulted in expansion of these intratumoral populations, with the T_RM-like subset displaying significantly enhanced cytotoxic capacity. T_RM-like CD8⁺ T cells could also provide local immune protection against tumor rechallenge and a T_RM gene signature extracted from tumor-free tissue was significantly associated with improved clinical outcomes in TNBC patients treated with checkpoint inhibitors.