Correlation Research Between Smoking And Immune Microenvironment And Prognosis Outcomes Of Immunotherapy In Non-small Cell Lung Cancer

Lung cancer is the most common malignant tumor in the world and the main cause of cancer-related deaths.Statistics show that 80%of newly diagnosed lung cancer patients have the non-small cell lung cancer(NSCLC)subtype.Immune checkpoint inhibitors(ICIs)have been found to be effective treatments of advanced NSCLC which prolong the survival of patients,and have become the standard treatment choice for patients with advanced NSCLC.Currently,it is not clear which patients can benefit from ICI treatment.The expression level of PD-L1,tumor mutation load(TMB),microsatellite instability(MSI)and DNA mismatch repair(dMMR)have been approved to be predictors of the efficacy of ICIs in patients with NSCLC.However,these predictors have certain limitations such as,lack of standardized detection methods and evaluation criteria.Therefore,there is a need to identify patients likely to benefit from ICIs.Smoking status has been confirmed to affect the efficacy of ICIs in NSCLC patients,but the specific mechanism is unclear.In this study,we analyzed the Memorial Sloan Kettering Cancer Center(MSKCC)clinical NSCLC cohort receiving ICI treatment.The Cancer Genome Atlas(TCGA)Pan-Lung Cancer cohort,and GSE41271 lung cancer cohort from the Gene Expression Omnibus(GEO)database who did not receive ICI treatment.The following data were extracted;survival prognosis,gene mutation,copy number variation,immunogenicity,and immune microenvironment.The impact of smoking status on the prognosis of NSCLC patients treated with ICIs and possible mechanism was explored.In addition.8 fresh NSCLC surgical tissue samples were collected for mass cytometry(CyTOF)experiments to further characterize the immune characteristics and verify the mechanism.We found that smokers among NSCLC patients whoc received ICI treatment had longer progression-free survival(HR:0.69.95%CI:0.49-0.97.p=0.03 1)compared with those who never smoked.Further analysis of the TCGA and GEO validation cohorts showed that the differences in prognosis between different groups may be related to the smoking group’s higher immunogenicity,higher gene mutations,and stronger immune microenvironment TP53 was significantly mutated in the smoking group for MSKCC and TCGA data sets,and both were the genes with the highest mutation rate in the two data sets.CIBERSORT analysis of TCGA and GEO data sets showed that several cells were involved in immune response processes,such as eosinophils,activated mast cells,neutrophils,B cells,M0 macrophages,M1 macrophages,and activated CD4+ T cells.These cells exhibited high infiltration in the smoking group,whereas immunosuppressive cells,M2 macrophages,and regulatory T cells showed high infiltration in the non-smoking group.The results of the CyTOF experiment further demonstrated that the immune microenvironment of the smoking group was characterized by high expression of immune positive regulatory chemokine and abundance of immune activated cells,including follicular helper CD4+T cells,gamma delta CD4+T cells,activated DC,and activated CD8+T cells.In contrast,the immune microenvironment of the non-smoking group was significantly enriched with immunosuppression-related cells,including regulatory T cells and M2 macrophages.Finally,we found high enrichment of CD45RAhighCD4+T cells and CD45RAhighCD8+T cells in the non-smoking group.In summary,our results suggest that the smoking group of NSCLC patients receiving ICI treatment has better prognosis due to their stronger immunogenicity and activated immune microenvironment.