Background: The dominant subclass of non-small-cell lung cancer (NSCLC) is lung adenocarcinoma (LUAD). The tumor microenvironment (TME) is a crucial feature of carcinogenesis and progression in LUAD. Furthermore, immune and stromal components of TME are crucial factors to investigating and curing LUAD. Thus, the study assessed the value of TME-related genes for LUAD prognosis and immune infiltration.

Methods: All data were downloaded from TCGA and GEO databases. The immune and stromal scores were downloaded from ESTIMATE, and the association between the scores and prognosis was explored by Kaplan-Meier survival analysis. Protein-protein interaction (PPI) network and univariate Cox regression were used to find TME-related differentially expressed genes (DEGs), and HLA-DMA was regarded as a prognostic hub gene. Western blot analyses, qRT-PCR, and immunofluorescence were applied to verify HLA-DMA expression in clinical samples. NSCLC cell lines were used to verify the effect of HLA-DMA on cell proliferation and cell cycle distribution. At last, the alteration of immunotherapy response and TME transition caused by HLA-DMA different expression were further studied.

Results: The immune score was positively correlated with survival. The functional analyses suggested that TME-related DEGs may be involved in the immune response. The expression level of HLA-DMA was decreased in LUAD. In addition, HLA-DMA expression was associated with several clinical features and was positively associated with survival. Furthermore, HLA-DMA may suspend cell proliferation by regulating cell cycle. HLA-DMA expression was closely associated with immune infiltration and positively correlated with TMB, indicating that patients with high HLA-DMA level were more suitable for immunotherapy.

Conclusion: These results reveal that HLA-DMA might act as a biomarker for immune infiltration and immunotherapy response.