Abstract

BackgroundTo date, immunotherapy has improved the 5-year survival rate of patients with advanced non-small cell lung cancer (NSCLC) from 4% to 15%. However, only 30%-50% of the NSCLC patients respond to immune checkpoint inhibitors (ICIs) immunotherapy. Therefore, screening patients for potential benefit with precise biomarkers may be of great value.MethodsFirst, an immunotherapy NSCLC cohort was analyzed to identify the gene mutations associated with the prognosis of ICI treatment. Further analyses were conducted using NSCLC cohort in The Cancer Genome Atlas (TCGA) project to validate the correlations between the specific gene mutations and tumor immunogenicity, antitumor immunity, and alterations in the tumor-related pathways using Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and Gene set enrichment analysis (GSEA).ResultsIn the immunotherapy NSCLC cohort (n = 266), significantly longer overall survival (OS) rates were observed in the PAK7-mutant type (PAK7-MT) group (n = 13) than the PAK7-wild type (PAK7-WT) group (n = 253) (P = 0.049, HR = 0.43, 95%CI = 0.23-0.79). In the TCGA cohort, PAK7 mutations were correlated with the higher tumor mutation burden (TMB) (14.18 vs. 7.13, P <0.001), increased neoantigen load (NAL) (7.52 vs. 4.30, P <0.001), lower copy number variation (CNV), and higher mutation rate in the DNA damage response (DDR)-related pathways. In addition, PAK7 mutations were also positively correlated with immune-related genes expressions and infiltrating CD8+ T cells (0.079 vs. 0.054, P = 0.005). GSEA results showed that several tumor-related pathways varied in the PAK7-MT group, suggesting the potential mechanisms that regulate the tumor immune-microenvironment.ConclusionsThis study suggested that the PAK7 mutations might be a potential biomarker to predict the efficacy of immunotherapy for NSCLC patients. Considering the heterogeneity among the patients and other confounding factors, a prospective clinical trial is proposed to further validate the impact of PAK7 mutation on the immunotherapy outcomes in NSCLC.

Highlights

  • Lung cancer has the highest incidence and mortality rates among malignant tumors worldwide, in which non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancers [1]

  • P21-activated kinase 7 (PAK7) Mutations Are Associated With a Favorable Prognosis in the NSCLC Patients Receiving immune checkpoint inhibitors (ICIs)

  • Survival analyses were conducted for the MSKCC-IO and TCGA cohorts based on the available clinical and mutation data to investigate the correlations between PAK7 mutation and clinical outcomes of NSCLC patients

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Summary

Introduction

Lung cancer has the highest incidence and mortality rates among malignant tumors worldwide, in which non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancers [1]. Immune checkpoint inhibitors (ICIs) exhibit durable antitumor effects by activating T cells Their response rate in the advanced NSCLC is approximately 30-50% [5,6,7], which means that quite many patients cannot benefit from this immunotherapy. Some biomarkers have successfully predicted the efficacy of ICI treatment to various degrees [8], such as PD-L1 expression, tumor mutation burden (TMB), neoantigen load (NAL), mismatch repair (MMR) status, microsatellite instability (MSI) status, specific gene mutations, and tumorinfiltrating lymphocytes (TILs). These potential biomarkers still have some limitations. Screening patients for potential benefit with precise biomarkers may be of great value

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