RESUMEN

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.

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RESUMEN

The peripheral T-cell pool consists of several, functionally distinct populations of CD8+ T cells. CD44 and CD62L are among the major surface markers that allow us to define T-cell populations. The expression of these molecules depends on the functional status of a T lymphocyte. Under lymphopenic conditions, peripheral T cells undergo homeostatic proliferation and acquire the memory-like surface phenotype CD44hiCD62Lhi. However, the data on the functional activity of these cells remains controversial. In this paper, we analyzed the effects of the adoptive transfer of syngeneic splenocytes on the recovery of CD8+ T cells in sublethally irradiated mice. Our data demonstrate that under lymphopenia, donor lymphocytes form a population of memory-like CD8+ T cells with the phenotype CD122+CD5+CD49dhiCXCR3+ that shares the phenotypic characteristics of true memory cells and suppressive CD8+ T cells. Ex vivo experiments showed that after adoptive transfer in irradiated mice, T cells lacked the functions of true effector or memory cells; the allogeneic immune response and immune response to pathogens were greatly suppressed in these mice.