Ovarian cancer immunogenicity is governed by a narrow subset of progenitor tissue-resident memory T cells

Carmen M. Anadon, Xiaoqing Yu, Kay Hänggi, Subir Biswas, Ricardo A. Chaurio, Alexandra Martin, Kyle K. Payne, Gunjan Mandal, Patrick Innamarato, Carly M. Harro, Jessica A. Mine, Kimberly B. Sprenger, Carla Cortina, John J. Powers, Tara Lee Costich, Bradford A. Perez, Chandler D. Gatenbee, Sandhya Prabhakaran, Douglas Marchion, Mirjam H.M. HeemskerkTyler J. Curiel, Alexander R. Anderson, Robert M. Wenham, Paulo C. Rodriguez, Jose R. Conejo-Garcia

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Despite repeated associations between T cell infiltration and outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that the 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 shows that only progenitor (TCF1low) tissue-resident T cells (TRMstem cells), but not recirculating TCF1+ T cells, predict ovarian cancer outcome. TRMstem cells arise from transitional recirculating 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, but 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-like cells. Our results define the signature of relevant tumor-reactive T cells in human ovarian cancer, which could be applicable to other tumors with unideal mutational burden.

Original languageEnglish (US)
Pages (from-to)545-557.e13
JournalCancer Cell
Volume40
Issue number5
DOIs
StatePublished - May 9 2022

Keywords

  • immuno-oncology
  • neoantigen
  • ovarian cancer
  • tissue-resident memory-like T cell
  • tumor-infiltrating lymphocyte

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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