Tumor stage-driven disruption of NK cell maturation and cytotoxic functions in the lung tumor microenvironment

Natural Killer (NK) cells play a pivotal role against cancer, both by direct killing of malignant cells and by promoting adaptive immune response though cytokine and chemokine secretion. In the lung tumor microenvironment (TME), NK cells are scarce and dysfunctional, but the underlying mechanisms are still unclear. By conducting single-cell transcriptomic analysis of lung tumors, and exploring pseudotime, we uncovered that the TME disrupts the maturation trajectory of NK cells in a tumor stage-dependent manner, ultimately resulting in the selective exclusion of the cytotoxic subset. Using functional assays, we observed intratumoral NK cell death and a reduction in cytotoxic capacities depending the tumor stage. Finally, our analyses of human public dataset on lung cancer corroborate these findings, revealing a parallel dysfunctional maturation process of NK cells during tumor progression. These results highlight novel mechanisms by which tumor cells escape from NK cell cytotoxicity, therefore paving the way for tailored therapeutic strategies. Mice with small or large tumors (see Material and Methods) were sacrificed. Tumoral, and non-tumoral counterpart, parts of the lungs were analyzed in this single-cell experiment *************************************************************** Submitter states that missing raw files are due to file loss. ***************************************************************