AUTHOR=Zhou Lin-Zhi , Xiao Hong-Qi , Chen Jie 

TITLE=Mismatch repair gene MSH6 correlates with the prognosis, immune status and immune checkpoint inhibitors response of endometrial cancer

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1302797

DOI=10.3389/fimmu.2024.1302797

ISSN=1664-3224

ABSTRACT=<sec><title>Objective</title><p>Many patients treated with immune checkpoint inhibitors (ICIs) developed primary or secondary drug resistance for unknown reasons. This study investigates whether mismatch repair (MMR) genes are responsible for this therapeutic restriction.</p></sec><sec><title>Methods</title><p>We obtained the transcriptional, clinical and single nucleotide polymorphism data for endometrial cancer (EC) from The Cancer Genome Atlas and the immunophenoscore data of EC from The Cancer Immunome Atlas, then analyzed in R to evaluate the relationship between MMR genes and clinicopathological features, prognosis, immune infiltration, immune checkpoint expression and responsiveness to ICIs in EC. We used differentially expressed genes in the <italic>MSH6</italic> high and low expression groups to conduct GO and KEGG analyses to explore the impact of <italic>MSH6</italic> on the biological functions of EC. Finally, we verified the bioinformatics results with <italic>in vitro</italic> experiments.</p></sec><sec><title>Results</title><p>Our analyses showed that compared with the high <italic>MSH6</italic> expression group, the low <italic>MSH6</italic> expression group had better survival outcomes and less aggressive clinicopathological features. In the multivariate Cox analysis, <italic>MSH6</italic> was the only independent risk factor that could predict the prognosis of EC. Besides, the low <italic>MSH6</italic> expression group also had a higher immune score, more active immune infiltration and higher immune checkpoint expression, resulting in better responsiveness to ICIs treatment, consistent with the enrichment of GO terms and KEGG pathways related to immune response in this group. Meanwhile, the GO and KEGG enrichment results of the <italic>MSH6</italic> high expression group were associated with cell cycle, DNA damage repair and tumorigenesis. To exclude the influence of <italic>MSH6</italic> mutations, we performed the previous analyses on the <italic>MSH6</italic> wild-type tumor samples and obtained consistent results. <italic>In vitro</italic> experiments also confirmed that after knocking down <italic>MSH6</italic> in endometrial cancer cells, their proliferation, migration and invasion abilities were weakened, while the expression levels of PD-L1 and PD-L2 were elevated. In comparison, overexpression of <italic>MSH6</italic> showed an opposite trend.</p></sec><sec><title>Conclusion</title><p>Reduced <italic>MSH6</italic> expression could serve as a potential biomarker for predicting better prognosis, active immune status, higher immune checkpoint expression level and better responsiveness to ICIs treatment in EC. <italic>MSH6</italic> may become a potential target for treating solid tumors.</p></sec>