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.

尽管 T 细胞浸润与结果之间反复存在关联，但人类卵巢癌对免疫疗法的反应仍然很差。我们报告说，卵巢癌浸润性 T 细胞中肿瘤识别的标志主要限于组织驻留记忆 (TRM) 细胞。^{83,454 个 CD3 +} CD8 ⁺ CD103 ⁺ CD69 ⁺ TRM 细胞的单细胞 RNA/TCR/ATAC 测序和 122 个高级别浆液性卵巢癌的免疫组织化学显示只有祖细胞（TCF1^低）组织驻留 T 细胞（TRM_干细胞），但不是再循环的 TCF1 ⁺ T 细胞，预测卵巢癌的结果。TRM_阀杆细胞产生于过渡再循环 T 细胞，这取决于抗原亲和力/持久性，导致最终耗尽的寡克隆、嗜血细胞、效应淋巴细胞。因此，卵巢癌确实是一种免疫原性疾病，但这取决于约 13% 的 CD8 ⁺肿瘤浸润性 T 细胞（约 3% 的 CD8 ⁺克隆型），这些细胞针对高亲和力抗原并维持效应 TRM-波像细胞。我们的结果定义了人类卵巢癌中相关肿瘤反应性 T 细胞的特征，这可能适用于具有不理想突变负荷的其他肿瘤。