Correleation Of LRP1B Mutation With Tumor Immune Microenvironment And Prognosis Of Immune Checkpoint Inhibitors Therapy In Lung Adenocarcinoma

Objective Over the past decade,immune checkpoint inhibitors(ICIs)have emerged as a novel treatment option for lung malignancies,but unfortunately,only a fraction of patients benefit from them.Therefore,the most critical challenge is to identify patients most likely to respond to immune checkpoint inhibitor therapy before treatment.Specific genetic mutations can affect the efficacy of immune checkpoint inhibitor therapy,and this study aims to systematically analyze the LRP1B mutation and its association with the tumor immune microenvironment and ICIs therapy.Methods We collected a cohort of LUAD patients treated with ICIs(ICIs cohort)and a cohort of the Cancer Genome Atlas lung adenocarcinoma patients(TCGA-LUAD cohort).The LRP1B mutation was identified as our study target by prognostic analysis of common mutations in LUAD patients in the ICIs cohort.Pathway enrichment analysis and copy number variation analysis were used to assess immune-related pathway differences and genomic stability differences between patients with LRP1B mutations and those with LRP1B wild type.Next transcriptomic data analysis of TCGA-LUAD and CIBERSORT analysis compared the differences in tumor immune microenvironment between the LRP1B mutant and wild groups.Multiplex immunohistochemistry on clinical samples further validated the differences in the level of immune cell infiltration within the tumor.Analysis of tumor mutation burden,neoantigen load,and DNA damage repair pathway mutation counts compared tumor immunogenicity differences between the LRP1B mutation group and the wild group.Univariate and multivariate Cox regression analyses were performed in the ICIs cohort to determine the prognostic impact of LRP1B mutation on LUAD patients treated with ICIs.A nomogram was constructed combining the LRP1B mutation and the clinical characteristics of patients to predict the survival impact of ICIs treatment on LUAD patients.Receiver operating characteristic(ROC)curves as well as calibration curves were used to assess the accuracy of the constructed nomogram in estimating patient prognosis.Results Prognostic analysis showed a strong correlation between LRP1B mutation and prolonged progression-free survival in LUAD patients treated with ICIs(median time 24.0 months vs.4.11 months,P=0.0016).The results of pathway enrichment analysis and copy number variation analysis indicated that LRP1B mutation was associated with activation of immune-related pathways and higher genomic instability.Transcriptome data analysis and CIBERSORT analysis revealed higher expression of immune-related genes and immune checkpoint-related genes in LUAD tumor tissues with LRP1B mutated type,along with higher levels of activated immune cell infiltration.Multiplex immunohistochemical results of clinical samples demonstrated that LRP1B mutation was associated with increased levels of CD8+T cell(P<0.01)and PD-L1+CD68+macrophage(P<0.05)infiltration in the LUAD tumor microenvironment.Analysis of tumor mutation burden,neoantigen load,and DNA damage repair pathway mutation counts indicated that LUAD patients with LRP1B mutation had higher tumor immunogenicity.Univariate Cox regression(HR=0.265,95%CI:0.110-0.638,P=0.003)and multivariate Cox regression(HR=0.232,95%CI:0.084-0.645,P=0.005)analyses illustrated that LRP1B mutation was an independent prognostic factor for progression-free survival in LUAD patients treated with ICIs.Nomogram constructed by combining LRP1B mutation and patient clinical characteristics were effective in predicting the survival impact of ICIs treatment on LUAD patients with high accuracy,with area under the curve(AUC)values of 0.823 and 0.840 at 1 and 2 years,respectively.Conclusion(1)LRP1B mutation is associated with high expression of immune-related genes and high levels of immune cell infiltration in the tumor immune microenvironment of LUAD patients.(2)LRP1B mutation is associated with high immunogenicity in LUAD patients and can predict treatment response and prognosis in LUAD patients treated with ICIs.(3)Nomogram combining LRP1B mutation status and clinically relevant features has high accuracy and is potentially valuable for predicting progression-free survival in LUAD patients treated with ICIs.(4)For patients with intermediate to advanced LUAD,in addition to detecting PD-L1 expression and tumor mutation burden or neoantigen load,the mutation status of LRP1B can also be included in the reference to assess whether patients are suitable for treatment with ICIs.