Tumor-infiltrating NK cell subsets associated with the magnitude of T cell response in human lung cancer

NK cells are the predominant innate lymphocyte subset that contribute to anti-tumor immunity. The molecular profile of human tumor-infiltrating NK cells, and particularly, their characteristics in relation to CD8+ cytotoxic T lymphocyte (CTL) density within tumors is poorly understood. Here, we performed single-cell and bulk transcriptomic analysis of NK cells within tumor and adjacent normal lung tissue from patients with treatment-naïve lung cancer. We found divergent NK cell subsets with distinct functional features that were associated with the magnitude of CD8+ CTL response in tumors. CD16pos NK cells present in tumors with high density of CD8+ CTLs were enriched for transcripts linked to cytotoxicity, pro-inflammatory chemokines and effector function. CD16neg NK cells predominantly infiltrated tumors relative to lung tissue and harbored sub-populations with unique gene expression programs. Notably, tumors with high density of CD8+ CTLs were enriched for a CD16neg NK cell subset with features of tissue residency and NK cell memory as well as a CD16neg ILC3-like subset that displayed transcriptional features linked to activation, NFκB signaling, dendritic cell recruitment and lymphoid-tissue inducing properties. These data reveal that a potentially synergistic NK cell innate immune program may co-operate with CD8+ CTLs to mediate tumor clearance in tumors with a high tumor-infiltrating lymphocyte (TIL) density.