Intratumoral CD8+ T cells with a tissue-resident phenotype mediate local immunity and immune checkpoint responses in breast cancer

CD8+ tumor-infiltrating lymphocytes with a tissue-resident memory T (TRM) cell phenotype are associated with favorable prognosis in patients with triple negative breast cancer (TNBC). However, the relative contribution of CD8+ TRM 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 triple-negative breast cancer patients. Phenotypic and transcriptional studies established two intratumoral sub-populations: one more enriched in markers of terminal exhaustion (TEX-like) and the other with a bona-fide resident phenotype (TRM-like). Treatment with anti-PD-1 and anti-CTLA-4 therapy resulted in a expansion of these intratumoral populations, with the TRM-like subset displaying significantly enhanced cytotoxic capacity. Importantly, we demonstrate that it is the TRM-like CD8+ T cells can provide local immune protection against mammary tumor re-challenge and that a gene signature from remaining TRM-like CD8+ T cells extracted from tumor-free tissue was significantly associated with improved outcomes in human TNBC patients treated with checkpoint inhibition. Overall, our data suggest that CD8+ T cells with a tissue resident phenotype play a critical role in response to local immunosurveillance and responses to immune checkpoint blockade in breast cancer.