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. Identifying biomarkers is crucial to improve outcomes. This study systematically analyzes LRP1B mutation and its association with the tumor immune microenvironment (TIME) and immunotherapy in LUAD. Methods: We analyzed a cohort of 59 LUAD patients treated with immune checkpoint inhibitors (ICIs) (PD-1 plus CTLA-4) to assess associations between LRP1B mutation and prognosis. We also evaluated a TCGA-LUAD cohort (n=507) with genomic, transcriptomic, and survival data. Between LRP1B-mutated (MT) and wild-type (WT) groups, we compared mutation profiles, immunogenicity (TMB, neoantigen load), TIME features, and DNA damage repair (DDR) pathway mutations. Multiplex immunohistochemistry (mIHC) on 20 clinical LUAD specimens validated microenvironmental differences. Results: LRP1B mutation associated with multiple immune-related pathways. LRP1B-MT LUAD showed higher expression of genes involved in antigen presentation, cytotoxicity, chemokines, and pro-inflammatory mediators; some immune checkpoint genes were also upregulated. CIBERSORT indicated higher infiltration of activated immune cells in LRP1B-MT tumors. mIHC confirmed elevated PD-L1 expression and immune cell infiltration in LRP1B-MT tumors. Patients with LRP1B mutation had higher tumor mutational burden (TMB), more neoantigens, and more mutations in DDR pathways. In the ICIs cohort, LRP1B mutation was associated with significantly prolonged progression-free survival (PFS) and better response metrics. A nomogram incorporating LRP1B status predicted PFS with good discrimination. Conclusions: LRP1B mutation is associated with higher immune cell infiltration and elevated immune gene expression within the TIME and may serve as a prognostic biomarker for LUAD patients treated with ICIs.