AUTHOR=Ji Wenxiang , Niu Xiaomin , Yu Yongfeng , Li Ziming , Gu LinPing , Lu Shun 

TITLE=SMO mutation predicts the effect of immune checkpoint inhibitor: From NSCLC to multiple cancers

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.955800

DOI=10.3389/fimmu.2022.955800

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>The emergence of immune checkpoint inhibitors (ICIs) is one of the most promising breakthroughs for the treatment of multiple cancer types, but responses vary. Growing evidence points to a link between developmental signaling pathway-related genes and antitumor immunity, but the association between the genomic alterations in these genes and the response to ICIs still needs to be elucidated.</p></sec><sec><title>Methods</title><p>Clinical data and sequencing data from published studies and our cohort were collected to analyze the association of the mutation status of <italic>SMO</italic> with the efficacy of ICI therapy in the non-small cell lung cancer (NSCLC) cohort and the pan-cancer cohort. Furthermore, the correlation between <italic>SMO</italic> mutation and immunotherapeutic biomarkers such as immune cell infiltration, immune-related genes, and underlying signaling pathways was analyzed. Three <italic>SMO</italic> mutant plasmids were transfected into cells to explore the <italic>SMO</italic> mutation status in the context of its expression and cell growth.</p></sec><sec><title>Result</title><p>In the NSCLC discovery cohort, the median progression-free survival in the <italic>SMO</italic> mutant (SMO_MUT) was longer than that in the wild type (SMO_WT) (23.0 vs. 3.8 months, adjusted <italic>p</italic> = 0.041). This finding was further confirmed in the NSCLC validation cohort (8.7 vs. 5.1 months, adjusted <italic>p</italic> = 0.013). In the pan-cancer cohort (<italic>n</italic> = 1,347), a significant overall survival advantage was observed in patients with <italic>SMO</italic> mutations [not reached (NR) vs. 18 months, adjusted <italic>p</italic> = 0.024]. In the subgroup analysis, the survival advantage of SMO_MUT against SMO_WT was prominent and consistent across genders, ages, treatment types, cancer types, and the tumor mutation burden (TMB) status (all <italic>p</italic><sub>interaction</sub> &gt; 0.05). In an <italic>in vitro</italic> experiment, we found that both the mutant and wild-type plasmids can promote the expression of <italic>SMO</italic>, but the mutant plasmid had lower <italic>SMO</italic> mRNA and protein levels than the wild type. In CCK-8 experiments, we found that SMO_MUT plasmids can improve the growth of Calu-1 and PC-9 cells, but this capability varied between different mutations and cells. Upon further exploration, the <italic>SMO</italic> mutation status was found to be related to a higher TMB, more neoantigen load, more DNA damage repair (DDR) mutations, higher microsatellite instability (MSI) score, and higher CD8<sup>+</sup> T-cell infiltration.</p></sec><sec><title>Conclusions</title><p>The <italic>SMO</italic> mutation status is an independent prognostic factor that can be used to predict better clinical outcomes of ICI treatment across multiple cancer types.</p></sec>