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

Abstract

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.

Location of CD39+ T cell sub-populations within tumours predict differential outcomes in non-small cell lung cancer

“…24 Similarly, a recent study in breast cancer demonstrates that CD39+CD103+ T cells are tumour specific, predict improved patient outcome in triple negative breast cancer and demonstrate that this cell population is responsive to immune checkpoint inhibition in vitro. 25 We have extended these findings to show that in NSCLC, CD39+ CD8+ T cells are confined to the stroma unless they co-express CD103 in which case they are able to infiltrate the tumour nest. Notably, the density of CD39+CD103+ CD8+ T cells in the tumour nest is linked to improved survival and RFS, while the density of CD103SP CD8+ T cells is not, further implying that CD39+CD103+ CD8+ T cells are the main tumour cell killing population in situ.…”

“…24 Similarly, a recent study in breast cancer demonstrates that CD39+CD103+ T cells are tumour specific, predict improved patient outcome in triple negative breast cancer and demonstrate that this cell population is responsive to immune checkpoint inhibition in vitro . 25…”

Supervised discovery of interpretable gene programs from single-cell data

“…These cells express clonal TCRs and specific markers (e.g. ENTPD1, CXCL13 ) 18,19 , and can accumulate upon PD-1/PD-L1 checkpoint blockade in a process called clonal expansion 20,21 . Conversely, T cells that expand clonally under ICT are likely to be tumor-reactive 17,20 .…”

“…ENTPD1, CXCL13 ) 18,19 , and can accumulate upon PD-1/PD-L1 checkpoint blockade in a process called clonal expansion 20,21 . Conversely, T cells that expand clonally under ICT are likely to be tumor-reactive 17,20 . These T cells may also gradually become exhausted (lose effector capacity) upon prolonged antigen exposure in the tumor microenvironment 22,23 .…”

“…a , t-SNE map of the entire dataset highlighting CD8 + T cells (left), and force-directed layout (FDL, n=43,066 cells) of CD8 + T cells labeled by evidence of clonal T-cell expansion in the donor (right). T cells that expand clonally under ICT are likely to be tumor-reactive 17,20 . b , c , FDL of CD8 + T cells (n=43,066) colored by tumor reactivity (left) or exhaustion (right) cell scores, and contour plots depicting cell score density distribution from patients with (red) or without (blue) clonal expansion of T cells under therapy.…”