Ovarian Cancer Immunogenicity is Governed by a Narrow Subset of Progenitor Tissue-Resident Memory T-Cells

Abstract

Despite repeated associations between T-cell infiltration and outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that hallmarks of tumor recognition in ovarian cancer-infiltrating T-cells are primarily restricted to tissue-resident memory (TRM) cells. Single-cell RNA/TCR/ATAC sequencing of 83,454 CD3+CD8+CD103+CD69+ TRM cells and immunohistochemistry of 122 high-grade serous ovarian cancers showed that only progenitor (TCF1low) tissue-resident T-cells (TRMstem cells), but not re-circulating TCF1+ T-cells, predict ovarian cancer outcome. TRMstem cells arise from transitional re-circulating T-cells, which depends on antigen affinity/persistence, resulting in oligoclonal, trogocytic, effector lymphocytes that eventually become exhausted. Therefore, ovarian cancer is indeed an immunogenic disease that depends on ~13% of CD8+ tumor-infiltrating T-cells (~3% of CD8+ clonotypes), which are primed against high-affinity antigens and maintain waves of effector TRM cells.