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. 2022 Sep 23:15:5541-5555.
doi: 10.2147/JIR.S379016. eCollection 2022.

B Cell Receptor Signaling Pathway Mutation as Prognosis Predictor of Immune Checkpoint Inhibitors in Lung Adenocarcinoma by Bioinformatic Analysis

Anqi Lin #  1 , Jianbo Fang #  1 , Quan Cheng  2   3 , Zaoqu Liu  4 , Peng Luo  1 , Jian Zhang  1
Affiliations

B Cell Receptor Signaling Pathway Mutation as Prognosis Predictor of Immune Checkpoint Inhibitors in Lung Adenocarcinoma by Bioinformatic Analysis

Anqi Lin et al. J Inflamm Res. .

Abstract

Purpose: The advent of immune checkpoint inhibitors (ICIs) is a revolutionary breakthrough. However, without the selection of a specific target population, the response rate of ICI therapy in lung adenocarcinoma (LUAD) is low, so a clinical challenge has arisen in effectively using biomarkers to determine which patients can benefit from ICI therapy.

Methods: In this study, patients were divided according to whether or not nonsynonymous mutations were present in the BCR signaling pathway, and univariate and multivariate Cox regression models were established based on a LUAD cohort treated with ICIs (Miao-LUAD). Then the relationship between the mutation status of the BCR signaling pathway and the prognosis of immunotherapy was examined. Finally, data from The Cancer Genome Atlas (TCGA) LUAD cohort, the Rizvi-LUAD, the Samstein-LUAD, and the Zhujiang Hospital of Southern Medical University LUAD (Local-LUAD) cohort were combined, and the mutation panorama, immunogenicity, tumor microenvironment (TME) and pathway enrichment analysis between the BCR signaling pathway mutant group (BCR signaling MUT) and the BCR signaling pathway wild group (BCR signaling WT) were comprehensively compared.

Results: It was found that, compared with the BCR signaling WT, the BCR signaling MUT had a significantly improved progression-free survival (PFS) rate and overall survival (OS) rate, higher immunogenicity (tumor mutational burden, neoantigen load, and DNA damage response signaling mutations), and anti-tumor immune microenvironment.

Conclusion: These results revealed that the mutation state of the BCR signaling pathway has potential as a biomarker to predict the efficacy of ICIs in LUAD.

Keywords: B cell receptor; biomarker; immune checkpoint inhibitor; microenvironment; non-small cell lung cancer.

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Conflict of interest statement

The authors declare no conflicts of interest in relation to this work and that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Work flowchart of clinical cohort establishment and subsequent analysis in this study.
Figure 2
Figure 2
The predictive value of clinical characteristics and the mutation status of the BCR signaling pathway for ICI efficacy. (A) Forest plot of the results of the univariate and multivariate Cox regression analyses in the Miao-LUAD cohort (ICI-treated cohort). The main portion of the forest plot presents the hazard ratios (HR) and 95% confidence intervals (95% CI). The p value represents the statistical significance of the variable. The HR indicates whether the factors are predictors of favorable (HR < 1) or poor (HR > 1) outcomes. KM survival curves for (B) PFS and (C) OS in 47 LUAD patients from the Miao-LUAD cohort.
Figure 3
Figure 3
Genomic profiles of 47 LUAD patients in the Miao-LUAD cohort. (A) The 20 genes with the highest mutation frequencies and corresponding clinical information. (B) Mutual exclusion co-occurrence analysis of the top 20 mutated genes. BCR signaling MUT, b cell receptor signaling mutation group, BCR signaling WT, b cell receptor signaling wild group (*p<0.05; **p<0.01; and ***p<0.001).
Figure 4
Figure 4
Comparison of TMB between the MUT and WT groups in the (A) Local-LUAD cohort, (B) Rizvi-LUAD cohort, (C) Samstein-LUAD cohort, and (D) TCGA-LUAD cohort. (E) Comparison of DDR related signaling pathways alterations between the MUT and WT groups in the TCGA-LUAD cohort. (F) Comparison of NAL between the MUT and WT groups in the TCGA-LUAD cohort. MUT, B cell receptor signaling pathway mutant type; WT, B cell receptor signaling pathway wild type; (*p<0.05; **p<0.01; ***p<0.001; and ****p<0.0001).
Figure 5
Figure 5
(A) Comparison of the proportions of immune cells estimated by the CIBERSORT method between MUT and WT groups in the TCGA-LUAD cohort. (B) Comparison of immune related scores between MUT and WT groups in the TCGA-LUAD cohort. The immune related scores are Th2 Cell, number of segment score and Homologous recombination score. (C) Results of ssGSEA analysis between MUT and WT groups in the TCGA-LUAD cohort (*p<0.05; **p<0.01; ***p<0.001; and ****p<0.0001; Wilcoxon rank-sum test).
Figure 6
Figure 6
(A and B) Comparison of GSEA analysis between MUT and WT groups in the TCGA-LUAD cohort. (C) Potential mechanism underlying the prognostic value of the BCR signaling pathway mutation.
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