Ovarian cancer immunogenicity is governed by a narrow subset of progenitor tissue-resident memory Tcells.

Abstract

Despite repeated associations between Tcell infiltration and outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that the hallmarks of tumor recognition in ovarian cancer-infiltrating Tcells 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 shows that only progenitor (TCF1low) tissue-resident Tcells (TRMstem cells), but not recirculating TCF1+ Tcells, predict ovarian cancer outcome. TRMstem cells arise from transitional recirculating Tcells, which depends on antigen affinity/persistence, resulting in oligoclonal, trogocytic, effector lymphocytes that eventually become exhausted. Therefore, ovarian cancer is indeed an immunogenic disease, but that depends on ∼13% of CD8+ tumor-infiltrating Tcells (∼3% of CD8+ clonotypes), which are primed against high-affinity antigens and maintain waves of effector TRM-like cells. Our results define the signature of relevant tumor-reactive Tcells in human ovarian cancer, which could be applicable to other tumors with unideal mutational burden.