Genetic and Immunological Characterization of Advanced NSCLC with SWItch/Sucrose NonFermentable Families Genetic Alterations and Its Impact on Response to Immune Checkpoint Inhibitors

Abstract Background Genetic alterations involving the SWItch/Sucrose NonFermentable (SWI/SNF) family are highly prevalent but understudied in non-small cell lung cancer (NSCLC), especially its controversial roles in the implication of immunotherapy. We aimed to comprehensively characterize the clinicopathologic features of SWI/SNF mutation and to investigate its impact on immunotherapy outcomes among NSCLC patients. Methods Mutational landscapes of the SWI/SNF family in the Chinese or Western NSCLC population were depicted and compared using large public cohorts with sequencing data. Meanwhile, 519 NSCLC patients who received at least one dose of ICIs were enrolled from Sun Yat-sen University Cancer Center (SYSUCC) to explore the impact of SWI/SNF family mutation on immunotherapy and to discover distinct subpopulations. Multiple publicly available cohorts were then used for external validation. Results SWI/SNF family mutation was strongly associated with EGFR wild-type NSCLC and its prevalence was significantly lower in Chinese compared to Western population (14.7% vs. 24.5%, p<0.001), even after excluding the EGFR-mutant NSCLC patients (19.7% vs. 26.9%, p<0.001). There was a significantly higher rate of co-mutations with TP53 (72.6% vs. 61.0%) or KEAP1/STK11(22.1% vs. 11.2%) and a higher TMB in the SWI/SNFmut than the SWI/SNFWT NSCLC. Although immunotherapy or chemoimmunotherapy appeared to provide better survival outcomes than mono-chemotherapy among SWI/SNFmut NSCLC patients (POPLAR/OAK cohort, median OS 6.44 vs. 10.97 months; SYSUCC cohort, median PFS: 6.93 vs. 8.70 months), non-significant even worse results were found when compared to the SWI/SNFWT NSCLC. Further analysis identified two distinct SWI/SNFmut subpopulations harboring TP53 or STK11/KEAP1 co-mutations that presented significantly favorable or undesirable immunotherapy outcomes, respectively. This finding was then validated in multiple external datasets. Tumor microenvironment analysis revealed that TP53 co-mutation is associated with stimulatory antitumor immunity, whereas STK11/KEAP1 co-mutation may confer a suppressive microenvironment. Conclusion SWI/SNF family mutation itself may not be a reliable indicator of response to ICIs. TP53 and STK11/KEAP1 co-mutations hold the potential to guide the use of immunotherapy and improve the precise management in advanced NSCLC patients harboring SWI/SNF mutations. Given the unsatisfying treatment outcome of ICIs, effective therapeutic methods are still warranted to be explored for advanced NSCLC with SWI/SNF mutations.