NKG2A inhibition promotes NK cell-CD8+ T cell interactions to improve anticancer immunity in ovarian carcinoma

Natural killer (NK) cells contribute to tumor immunosurveillance, yet their heterogeneity across cancer types remains incompletely understood. Transcriptomic, spatial, and functional assays reveal that non-small cell lung carcinoma (NSCLC) is enriched in NK cells that mediate clinically relevant effector functions, whereas high-grade serous ovarian carcinoma (HGSOC) contains dysfunctional NK cells that express co-inhibitory receptors including NKG2A. Analysis of HGSOC patient samples and syngeneic mouse models indicates a crosstalk between NK cells and CD8⁺ T cells critical for effective antitumor immunity. Depletion of either population leads to phenotypic impairment of the reciprocal one. Blocking NKG2A restores NK cell cytotoxicity and promotes CD8⁺ T cell responses, significantly improving the efficacy of PD-1 blockade in murine HGSOC models. Thus, NK cells and CD8⁺ T cells engage in a functional interplay of immunological relevance. Moreover, the NKG2A–HLA-E axis represents a clinically actionable immunological checkpoint in tumors with impaired NK cell functions. The phenotypic and functional heterogeneity of Natural Killer (NK) cells between immunologically distinct tumor types has not been extensively investigated. Here, the authors combine multi-omic approaches, analysis of patient cohorts, and preclinical mouse models, comparing HGSOC to NSCLC as putative checkpoint-resistant and sensitive tumours. They observe an enrichment in NKG2A+ NK cells in HGSOC and propose that its inhibition boosts NK cell-CD8+ T cell interactions for improved cancer immunotherapy.