Suppression of LKB1-mutant lung adenocarcinoma by natural killer cells from females.

BACKGROUND: This study addressed the enigma of sex differences in smoking-related lung cancer, particularly focusing on the low LKB1 mutation frequency in female patients with lung adenocarcinoma. METHODS: Sex bias was studied with a genetically engineered mouse model and various tail-vein injection models. Immune cells were analyzed by antibody-depletion study, flow cytometry, and immunofluorescence. The relevance of our findings to human disease was validated by evaluating various lung adenocarcinoma datasets. All statistical tests are 2-sided. RESULTS: A statistically significant percentage of females are resistant to LKB1-mutant tumor formation in our models, reflecting this sex difference in humans. Natural killer (NK) cells were identified as a critical factor in this sex-biased response. This sex difference was observed primarily in LKB1-mutant lung adenocarcinoma, probably due to their low major histocompatibility complex class I level, making them the ideal target for NK cells through the missing-self recognition. Although females resistant to LKB1-mutant lung adenocarcinoma formation did not have enhancement of any specific NK subpopulation, our immunofluorescence analysis revealed high numbers of NKs in female lungs even with the presence of LKB1-mutant lung adenocarcinoma. Our gene set enrichment analysis of The Cancer Genome Atlas-lung adenocarcinoma dataset also showed that female LKB1-mutant lung adenocarcinoma patients have a stronger NK-mediated response after adjusting for other male-female differences using the LKB1 wild-type lung adenocarcinoma dataset. CONCLUSION: Females have a stronger NK-mediated response against LKB1-mutant lung adenocarcinoma, which was present in our mouse model and the human lung adenocarcinoma dataset. This study revealed a novel role of NK cells in suppressing LKB1-mutant lung adenocarcinoma in females, which should be assessed in the clinical setting in the future.