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

Anadon, C.M.; Yu, X.Q.; Hanggi, K.; Biswas, S.; Chaurio, R.A.; Martin, A.; Payne, K.K.; Mandal, G.; Innamarato, P.; Harro, C.M.; Mine, J.A.; Sprenger, K.B.; Cortina, C.; Powers, J.J.; Costich, T.L.; Perez, B.A.; Gatenbee, C.D.; Prabhakaran, S.; Marchion, D.; Heemskerk, M.H.M.; Curiel, T.J.; Anderson, A.R.; Wenham, R.M.; Rodriguez, P.C.; Conejo-Garcia, J.R.

doi:doi:10.1016/j.ccell.2022.03.008

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 (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 similar to 13% of CD8(+) tumor-infiltrating T cells (similar to 3% of CD8(+) clonotypes), which are primed against high...Show moreDespite 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 (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 similar to 13% of CD8(+) tumor-infiltrating T cells (similar to 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.Show less

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