mutation predicts the effect of immune checkpoint inhibitor: From NSCLC to multiple cancers.

BACKGROUND

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.

METHODS

Clinical data and sequencing data from published studies and our cohort were collected to analyze the association of the mutation status of with the efficacy of ICI therapy in the non-small cell lung cancer (NSCLC) cohort and the pan-cancer cohort. Furthermore, the correlation between mutation and immunotherapeutic biomarkers such as immune cell infiltration, immune-related genes, and underlying signaling pathways was analyzed. Three mutant plasmids were transfected into cells to explore the mutation status in the context of its expression and cell growth.

RESULT

In the NSCLC discovery cohort, the median progression-free survival in the mutant (SMO_MUT) was longer than that in the wild type (SMO_WT) (23.0 vs. 3.8 months, adjusted  = 0.041). This finding was further confirmed in the NSCLC validation cohort (8.7 vs. 5.1 months, adjusted  = 0.013). In the pan-cancer cohort ( = 1,347), a significant overall survival advantage was observed in patients with mutations [not reached (NR) vs. 18 months, adjusted  = 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  > 0.05). In an experiment, we found that both the mutant and wild-type plasmids can promote the expression of , but the mutant plasmid had lower 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 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 T-cell infiltration.

CONCLUSIONS

The mutation status is an independent prognostic factor that can be used to predict better clinical outcomes of ICI treatment across multiple cancer types.