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

作者：Carmen M. Anadon, Xiaoqing Yu, Kay Hänggi, Subir Biswas, Ricardo A. Chaurio, Alexandra L. Martin, Kyle K. Payne, Gunjan Mandal, Patrick Innamarato, Carly M. Harro, Jessica A. Mine, Kimberly B. Sprenger, Carla Cortina, John Joseph Powers, Tara Lee Costich, Bradford A. Perez, Chandler Gatenbee, Sandhya Prabhakaran, Douglas C. Marchion, Mirjam H.M. Heemskerk, Tyler Jay Curiel, Alexander R.A. Anderson, Robert Michael Wenham, Paulo C. Rodrı́guez, Jose Ramon Conejo-Garcia · 发表于：Cancer Cell · 年份：2022 · DOI：10.1016/j.ccell.2022.03.008 · 被引用次数：182 · 研究领域：Immune Cell Function and Interaction、T-cell and B-cell Immunology、Single-cell and spatial transcriptomics

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 (TCF1 low ) tissue-resident T cells (TRM stem cells), but not recirculating TCF1 + T cells, predict ovarian cancer outcome. TRM stem 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.