Dataset Information

CD39⁺PD-1⁺CD8⁺ T cells mediate metastatic dormancy in breast cancer.

ABSTRACT: Some breast tumors metastasize aggressively whereas others remain dormant for years. The mechanism governing metastatic dormancy remains largely unknown. Through high-parametric single-cell mapping in mice, we identify a discrete population of CD39⁺PD-1⁺CD8⁺ T cells in primary tumors and in dormant metastasis, which is hardly found in aggressively metastasizing tumors. Using blocking antibodies, we find that dormancy depends on TNF? and IFN?. Immunotherapy reduces the number of dormant cancer cells in the lungs. Adoptive transfer of purified CD39⁺PD-1⁺CD8⁺ T cells prevents metastatic outgrowth. In human breast cancer, the frequency of CD39⁺PD-1⁺CD8⁺ but not total CD8⁺ T cells correlates with delayed metastatic relapse after resection (disease-free survival), thus underlining the biological relevance of CD39⁺PD-1⁺CD8⁺ T cells for controlling experimental and human breast cancer. Thus, we suggest that a primary breast tumor could prime a systemic, CD39⁺PD-1⁺CD8⁺ T cell response that favors metastatic dormancy in the lungs.

SUBMITTER: Tallon de Lara P

PROVIDER: S-EPMC7859213 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

CD39+PD-1+CD8+ T cells mediate metastatic dormancy in breast cancer.

Tallón de Lara Paulino P Castañón Héctor H Vermeer Marijne M Núñez Nicolás N Silina Karina K Sobottka Bettina B Urdinez Joaquín J Cecconi Virginia V Yagita Hideo H Movahedian Attar Farkhondeh F Hiltbrunner Stefanie S Glarner Isabelle I Moch Holger H Tugues Sònia S Becher Burkhard B van den Broek Maries M

Nature communications 20210203 1

Some breast tumors metastasize aggressively whereas others remain dormant for years. The mechanism governing metastatic dormancy remains largely unknown. Through high-parametric single-cell mapping in mice, we identify a discrete population of CD39+PD-1+CD8+ T cells in primary tumors and in dormant metastasis, which is hardly found in aggressively metastasizing tumors. Using blocking antibodies, we find that dormancy depends on TNFα and IFNγ. Immunotherapy reduce ...[more]

PMID: 33536445

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Project description:Background: The relationship between the interleukin 17 (IL-17) family of cytokines and breast cancer has been widely studied in recent years. Many studies have revealed increased levels of the cytokine IL-17A in estrogen receptor (ER)-negative or triple-negative breast cancer. Upregulation of IL-17A signaling is associated with increased expression of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) in breast cancer with low ER expression and may elevate the infiltration of CD8+ T cells in tumor tissue. This study aims to determine whether ER downregulates the expression of PD-1/PD-L1, reduces the infiltration of CD8+ T cells, and affects the immune microenvironment by decreasing T-helper 17 (Th17) cell infiltration and inhibiting IL-17 signaling in breast cancer. Methods: Samples in The Cancer Genome Atlas Breast Cancer dataset were grouped by ER status and the PAM50 intrinsic subtype. The expression of IL-17 family cytokines and Th17 cell signature cytokines were compared between groups. IL-17 signaling pathway-related genes that were differentially expressed according to the ER level were identified. The PD-1 and PD-L1 levels were compared between breast cancer samples with different ER statuses and IL-17A/IL-17F expression levels. Correlation analyses of the expression of PD-1/PD-L1 and IL-17 signaling pathway-related genes were performed. The associations of the expression of IL-17 signaling pathway-related genes with the immune microenvironment were investigated. Results: High levels of ER decreased the expression of IL-17A, IL-17C, and IL-17F but increased the expression of IL-17E (IL25), which acts as a suppressor of IL-17 signaling. The expression levels of Th17 cell signature cytokines were significantly increased in ER-negative breast cancer. The expression levels of genes encoding downstream products of IL-17A/IL-17F signaling were downregulated in breast cancer with high ER expression. Increased expression of PD-1/PD-L1 was associated with ER-negative status, IL-17A-positive status, IL-17F-positive status, and upregulation of IL-17 signaling pathway-related genes in breast cancer. Enhanced IL-17 signal transduction was associated with the elevation of CD8+ T cell infiltration and variation of the immune microenvironment of breast cancer. Conclusion: High estrogen receptor levels decrease PD-1/PD-L1 expression and CD8+ T cell infiltration by suppressing Th17 cell infiltration and IL-17 signal transduction in breast cancer.

Dataset Information

CD39⁺PD-1⁺CD8⁺ T cells mediate metastatic dormancy in breast cancer.

Publications

CD39<sup>+</sup>PD-1<sup>+</sup>CD8<sup>+</sup> T cells mediate metastatic dormancy in breast cancer.

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