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

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 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.