LRP1B mutation is associated with tumor immune microenvironment and progression-free survival in lung adenocarcinoma treated with immune checkpoint inhibitors.

BACKGROUND

Only a fraction of lung adenocarcinoma (LUAD) patients are eligible for immunotherapy. The identification of biomarkers for immunotherapy is crucial to improve patient outcomes. This study aims to systemically analyze mutation and its association with the tumor immune microenvironment (TIME) and immunotherapy.

METHODS

A cohort of immune checkpoint inhibitors (ICIs)-treated LUAD patients was analyzed to assess the association of mutation with immunotherapy prognosis. Another cohort of LUAD patients with genetic and transcriptomic data was also obtained from The Cancer Genome Atlas (TCGA). By investigating the ICIs and the TCGA-LUAD cohorts, we compared the differences in mutation profiles, immunogenicity, TIME, and DNA damage repair (DDR) mutations between the -mutated and wild-type groups. Additionally, we performed multiplex immunohistochemistry (mIHC) to validate the differences in the tumor microenvironment.

RESULTS

Our results revealed that mutation is associated with multiple immune-related pathways. Analysis of TIME indicated that LUAD patients with mutation expressed significant levels of genes involved in antigen presentation, cytotoxicity, chemokines, and pro-inflammatory mediators, whereas a few immune checkpoint genes were highly expressed in the -mutated group as well. Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) analysis indicated that -mutated LUAD patients had higher infiltration of active immune cells. Multiplex IHC analysis showed that -mutated LUAD patients had elevated programmed death ligand-1 (PD-L1) expression and immune cell infiltration. Patients with mutation had higher tumor mutation burden, neoantigens, as well as more mutated genes in the DDR-related pathways. Finally, -mutated LUAD patients showed a significant prolongation of progression-free survival (PFS) in the ICIs cohort and could be effectively predicted by our constructed nomogram.

CONCLUSIONS

Our study suggests that mutation is associated with higher immune cell infiltration and elevated immune gene expression in TIME and potentially serves as a prognostic biomarker for LUAD patients treated with ICIs.