Expressional regulation of NKG2DLs is associated with the tumor development and shortened overall survival in lung adenocarcinoma

Natural killer group 2D ligands (NKG2DLs) are expressed on tumor cells as a ligand for Natural killer group 2D (NKG2D) receptors. NKG2DLs interact with NKG2D to induce immune cell-mediated cytotoxicity for eliminating tumors. Studies demonstrated that tumor cells can reduce NKG2DLs' expression to escape from anti-tumor im-munity, leading to an aggressive cancer phenotype and poor prognosis in some cancers. However, these studies are limited and there is no comprehensive work on the regulation of NKG2DLs in lung adenocarcinoma (LUAD) which is one of the deadliest cancers worldwide. Here, we conducted an in silico analysis to evaluate the changes in NKG2DLs in LUAD by analyzing The Cancer Genome Atlas and the Gene Expression Omnibus datasets including tumor vs. normal comparisons, TNM stages, survival and infiltrating immune estimation profile. Re-sults indicated that some members of NKG2DL were downregulated in LUAD as compared to normal samples. We determined that MICA (MHC class I polypeptide-related sequence A) was the most and significantly down -regulated ligand among others and the results were nearly consistent with the different datasets which we used. Furthermore, survival analysis revealed that down-regulated MICA transcript expression might be one of the prognostic indicators of LUAD. Interestingly, according to the immune cell infiltrating analysis, there wasn't a direct correlation between the MICA transcript expression and immune cell infiltration, while for MICB there was. In addition, in genetic alteration, DNA methylation and miRNA analyses, we did not observe critical out-comes that would clarify the down-regulated MICA expression in detail. Regardless, this study is highly comprehensive and contributes valuable suggestions to further functional studies about the regulation of NKG2DLs and promising immunotherapeutic approaches in LUAD.

Automated summary

This study analyzed genomic and gene expression data to investigate the regulation of NKG2DLs in lung adenocarcinoma (LUAD). The results showed that NKG2DLs, particularly MICA, were downregulated in LUAD compared to normal samples. Downregulated MICA transcript expression may be a prognostic indicator for LUAD. However, the mechanisms underlying the downregulation of MICA were not clarified in this study.