AUTHOR=Zeng Hao , Tong Fan , Bin Yawen , Peng Ling , Gao Xuan , Xia Xuefeng , Yi Xin , Dong Xiaorong 

TITLE=The Predictive Value of PAK7 Mutation for Immune Checkpoint Inhibitors Therapy in Non-Small Cell Cancer

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.834142

DOI=10.3389/fimmu.2022.834142

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>To 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.</p></sec><sec><title>Methods</title><p>First, 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).</p></sec><sec><title>Results</title><p>In the immunotherapy NSCLC cohort (n = 266), significantly longer overall survival (OS) rates were observed in the <italic>PAK7</italic>-mutant type (PAK7-MT) group (n = 13) than the <italic>PAK7</italic>-wild type (PAK7-WT) group (n = 253) (<italic>P</italic> = 0.049, HR = 0.43, 95%CI = 0.23-0.79). In the TCGA cohort, <italic>PAK7</italic> mutations were correlated with the higher tumor mutation burden (TMB) (14.18 <italic>vs.</italic> 7.13, <italic>P &lt;</italic>0.001), increased neoantigen load (NAL) (7.52 <italic>vs.</italic> 4.30, <italic>P &lt;</italic>0.001), lower copy number variation (CNV), and higher mutation rate in the DNA damage response (DDR)-related pathways. In addition, <italic>PAK7</italic> mutations were also positively correlated with immune-related genes expressions and infiltrating CD8+ T cells (0.079 <italic>vs.</italic> 0.054, <italic>P</italic> = 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.</p></sec><sec><title>Conclusions</title><p>This study suggested that the <italic>PAK7</italic> 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 <italic>PAK7</italic> mutation on the immunotherapy outcomes in NSCLC.</p></sec>