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

Abstract

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 (LUAD).

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 LUAD datasets. All statistical tests are 2-sided.

Results: A significant percentage of females are resistant to LKB1-mutant tumor formation in our models, reflecting this sex difference in humans. NK cells were identified as a critical factor in this sex-biased response. This sex difference was observed primarily in LKB1-mutant LUADs, probably due to their low MHC-I level, making them the ideal target for NK cells through the "missing-self" recognition. While females resistant to LKB1-mutant LUAD 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 LUAD. Our GSEA analysis of TCGA-LUAD dataset also showed that female LKB1-mutant LUAD patients have a stronger NK-mediated response after adjusting for other male-female differences using LKB1-wild type LUAD dataset.

Conclusion: Females have a stronger NK-mediated response against LKB1-mutant LUAD, which was present both in our mouse model and the human LUAD dataset. This study revealed a novel role of NK cells in suppressing LKB1-mutant LUAD in females, which should be assessed in the clinical setting in the future.