CD39+ tissue-resident memory CD8+ T cells with a clonal overlap across compartments mediate antitumor immunity in breast cancer

Despite being a standard treatment option in breast cancer, immune checkpoint inhibitors (ICIs) are only efficacious for a subset of patients. To gain a better understanding of the antitumor immune response in breast cancer, we examined the heterogeneity of CD8(+) T cells in tumors, metastatic lymph nodes (mLNs), and peripheral blood from patients with early breast cancer (n = 131). Among tissue-resident memory CD8(+) T (T-RM) cells, including virus- and tumor-specific CD8(+) T cells, CD39 expression was observed in a tumor-specific and exhausted subpopulation in both tumors and mLNs. CD39(+) T-RM cells from tumors and mLNs exhibited a phenotypic similarity and clonally overlapped with each other. Moreover, tumor or mLN CD39(+) T-RM cells clonally overlapped with CD39(-) T-RM and non-T-R(M) cells in the same compartment, implying a tissue-specific differentiation process. These inter-subpopulationally overlapping CD39(+) T-RM clonotypes were frequently detected among effector memory CD8(+) T cells in peripheral blood, suggesting a systemic clonal overlap. CD39(+) T-RM cell enrichment was heterogeneous among molecular subtypes of breast cancer, which is associated with the different role of antitumor immune responses in each subtype. In vitro blockade of PD-1 and/or CTLA-4 effectively restored proliferation of CD39(+) T-RM cells and enhanced cytokine production by CD8(+) T cells from tumors or mLNs, particularly in the presence of CD39(+) T-RM enrichment. This suggests that CD39(+) T-RM cells have a capacity for functional restoration upon ICI treatment. Thus, our study indicates that CD39(+) T-RM cells with a clonal overlap across compartments are key players in antitumor immunity in breast cancer.