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_RM 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. Reinvigorate your CD39+ TRM: Immune checkpoint blockade (ICB) has only displayed efficacy in some subsets of patients with breast cancer, yet it is unclear why. Here, Lee et al. examined tissue-resident memory T cells (T_RM) in the tumors, lymph nodes, and blood of patients with early breast cancer, finding that tumor-specific CD8⁺ T_RM expressed CD39, CD69, and CD103. These CD39⁺ T_RM displayed an exhausted phenotype and overlapping TCR clonality in tumors and lymph nodes. CD39⁺ T_RM were enriched in triple-negative breast cancer (TNBC) samples, correlating to overall survival of patients with TNBC, and could be reinvigorated from exhaustion with the addition of ICB ex vivo. Together, these data suggest that patients with TNBC with high CD39⁺ T_RM signatures might be good candidates for ICB treatment. [ABSTRACT FROM AUTHOR]