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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 (TRM) 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+ TRM cells from tumors and mLNs exhibited a phenotypic similarity and clonally overlapped with each other. Moreover, tumor or mLN CD39+ TRM cells clonally overlapped with CD39− TRM and non-TRM cells in the same compartment, implying a tissue-specific differentiation process. These inter-subpopulationally overlapping CD39+ TRM clonotypes were frequently detected among effector memory CD8+ T cells in peripheral blood, suggesting a systemic clonal overlap. CD39+ TRM 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+ TRM cells and enhanced cytokine production by CD8+ T cells from tumors or mLNs, particularly in the presence of CD39+ TRM enrichment. This suggests that CD39+ TRM cells have a capacity for functional restoration upon ICI treatment. Thus, our study indicates that CD39+ TRM 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 (TRM) in the tumors, lymph nodes, and blood of patients with early breast cancer, finding that tumor-specific CD8+ TRM expressed CD39, CD69, and CD103. These CD39+ TRM displayed an exhausted phenotype and overlapping TCR clonality in tumors and lymph nodes. CD39+ TRM 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+ TRM signatures might be good candidates for ICB treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: This study provides information about the genetic alterations associated with disease recurrence in early stage HER2-positive breast cancer. We found seven upregulated and two downregulated differentially expressed genes in patients with recurrence. In addition, the tumor inflammation signature score and the scores of six immune-related breast cancer signatures were decreased in patients with recurrence. Our study offers insight into the underlying genetic background of recurrence risk and can help to develop effective risk-adapted therapeutic strategies in early stage HER2-positive breast cancer. We aimed to compare gene expression in primary tumors of patients with recurrence and nonrecurrence to gain insight into the biology of high-risk HER2-positive early breast cancer. Patients who underwent curative resection and received adjuvant trastuzumab for HER2-positive early breast cancer were evaluated. Gene expression analyses were performed using NanoString Technologies' nCounter Breast Cancer 360 Panel. PAM50 intrinsic subtypes and Breast Cancer Signatures including tumor inflammation signature (TIS) were evaluated. Of 247 patients, 28 (11.3%) had recurrence at a median follow-up of 54.2 months. Patients with pathological stage III, tumor size > 5 cm, axillary lymph node metastases, and hormone receptor-negativity were more frequently observed in the recurrent group compared with the nonrecurrent group. In patients with recurrence, seven genes were upregulated significantly, including WNT11, HAPLN1, FGF10, BBOX1, CXADR, NDP, and EREG, and two genes were downregulated, including CXCL9 and GNLY. TIS score was significantly lower in patients with recurrence compared with controls without recurrence. These findings suggest that activation of oncogenic signaling pathways related to cell proliferation, adhesion, cancer stemness, and noninflamed tumor microenvironment are associated with the risk of recurrence in early stage, HER2-positive breast cancer. [ABSTRACT FROM AUTHOR]