Correlation Study Between CDKN2A Mutation Combined With Tumor Microenvironment And Efficacy Of Immunotherapy In Advanced Squamous Cell Lung Cancer

BackgroundSquamous cell lung cancer(SQCC)accounts for approximately 20%to 30%of non-small cell lung cancer and has experienced the development of chemotherapy,targeted therapy,antiangiogenesis therapy and immunotherapy,but more effective treatment regimens are platinum-based chemotherapy and immunotherapy or immunochemotherapy.SQCC has complex genomic alterations,the most common mutated type is functional loss of TP53 and cyclin-dependent kinase inhibitor 2A(CDKN2A)mutations account for about 20%.CDKN2A is an important tumor suppressor gene,and its inactivation can cause the cell cycle to lose control and subsequent cell proliferation,which is closely related to the prognosis of cancer.However,the relationship between the alterations of CDKN2A and the efficacy of immunotherapy remains unclear.Studies found that PD-L1 and TMB can be as biomarkers for predicting response to immunotherapy,multiplex immunohistochemistry/immunofluorescence(mIHC/IF)has higher predictive value of the relationship between tumor microenvironment and the efficacy of immunotherapy.ObjectiveTo investigate the correlation between CDKN2A mutation combined with tumor microenvironment and the efficacy of immunotherapy in advanced squamous cell lung cancer.MethodsWe retrospectively analyzed clinical characteristics,treatment regimens and survival data of 143 patients with advanced SQCC between January 2015 and August 2019 at the Guangdong Provincial People’s Hospital.CDKN2A gene mutation was detected by Next-generation Sequencing,tumor microenvironment was detected by PD-L1,TMB and mIHC/IF.ResultsOf 143 patients with advanced SQCC,median age was 61 years(range:31-79 years old),131(92%)patients were male,117(82%)patients had a history of smoking,and median OS was 12.0 months.65 patients received immunotherapy and 78 did not.The median OS in both groups was 15.4 vs.10.0 months,P=0.060.Median OS was significantly prolonged in patients received immunotherapy than those didn’t receive immunotherapy of smokers(15.4 vs.8.4 months,HR=0.598;P--0.014)and PS 0-1 groups(16.0 vs.10.0 months,HR=0.671;P=0.041).43 patients received NGS test,TP53,PIK3CA,CDKN2A mutations were common in advanced SQCC(79%,28%and 26%,respectively).The OS in the CDKN2A-mutation group(n=11)and the Non-CDKN2A-mutation group(n=32)was 19.0 vs.10.6 months,P=0.101.Meanwhile,there were both not significant differences in PFS(6.9 vs.5.1 months;P=0.504)and OS(19.0 vs.15.4 months;P=0.133)between CDKN2A-mutation group and the Non-CDAN2A-mutation group in the immunotherapy arm.Patients in the strong PD-L1 expression group had significantly longer OS than those in the weak expression group(29.1 vs.10.1 months,HR=0.396,P=0.045).5 samples of advanced SQCC were detected by mIHC/IF,the number of CD3+T cell in the stroma region was higher than in the tumor region,CD3+T cell and M1-macrophages had high level expression in tumor microenvironmentConclusionsPatients with advanced squamous cell lung cancer who smoke and have good PS status can significantly benefit from immunotherapy.CDKN2A mutation has no significant correlation with immunotherapy efficacy and survival prognosis.Patients with strong PD-L1 expression had significantly longer OS than than those with weak expression,which can be used as an independent molecular marker for immunotherapy.