Tissue‐resident CD69(+)CXCR6(+) Natural Killer cells with exhausted phenotype accumulate in human non‐small cell lung cancer

Natural killer (NK) cells with tissue‐residency features (trNK cells) are a new subpopulation of NK cells, which plays an important role in tissue homeostasis. However, the characteristics of trNK cells in the tumor microenvironment (TME) of human cancers remain unclear. Using multicolor flow cytometry, we investigated the quantity, phenotype, and function of trNK cells in biospecimens freshly resected from 60 non‐small cell lung cancer (NSCLC) patients. We successfully identified a new CD69(+)CXCR6(+) trNK subset with an immunomodulatory‐like and exhausted phenotype, specifically accumulated in the TME of NSCLC. In vitro experiments showed that CD69(+)CXCR6(+) trNK cells more readily secreted IFN‐γ and TNF‐α spontaneously. Furthermore, the production of IFN‐γ and TNF‐α by tumor‐infiltrating CD69(+)CXCR6(+) trNK cells was not induced by their reactivation in vitro, which is analogous to T‐cell exhaustion. Finally, we demonstrated that the dysfunction of CD69(+)CXCR6(+) trNK cells could be partly ameliorated by PD‐1 and CTLA‐4 blockade. In summary, we identified a new dysfunctional CD69(+)CXCR6(+) trNK cell subset that specifically accumulates in the TME of NSCLC. Our findings suggest that CD69(+)CXCR6(+) trNK cells are a promising target for immune checkpoint inhibitors in the treatment of NSCLC.