Abstract
Background: The emergence of immune checkpoint inhibitors (ICIs) has opened a new chapter for the treatment of non-small cell lung cancer (NSCLC), and the best beneficiaries of ICI treatment are still being explored. Smoking status has been repeatedly confirmed to affect the efficacy of ICIs in NSCLC patients, but the specific mechanism is still unclear.Methods: We performed analysis on the Memorial Sloan Kettering Cancer Center (MSKCC) clinical NSCLC cohort receiving ICI treatment, The Cancer Genome Atlas (TCGA) Pan-Lung Cancer cohort, and Gene Expression Omnibus (GEO) database GSE41271 lung cancer cohort that did not receive ICI treatment, including survival prognosis, gene mutation, copy number variation, immunogenicity, and immune microenvironment, and explored the impact of smoking status on the prognosis of NSCLC patients treated with ICIs and possible mechanism. 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.Result: Through the analysis of the clinical data of the NSCLC cohort treated with ICIs in MSKCC, it was found that the smokers in NSCLC receiving ICI treatment had a longer progression-free survival (HR: 0.69, 95% CI: 0.49–0.97, p = 0.031) than those who never smoked. Further analysis of the TCGA and GEO validation cohorts found 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. The results of the CyTOF experiment further found that the immune microenvironment of smoking group was characterized by higher expression of immune positive regulatory chemokine, and higher 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 non-smoking group was significantly enriched for immunosuppressive related cells, including regulatory T cells and M2 macrophages. Finally, we also found highly enriched CD45RAhighCD4+ T cells and CD45RAhighCD8+ T cells in the non-smoking group.Conclusion: Our research results suggest that among NSCLC patients receiving ICI treatment, the stronger immunogenicity and activated immune microenvironment of the smoking group make their prognosis better.
Highlights
Lung cancer is one of the most frequently occurring types of tumor malignancy with the highest incidence worldwide
Three of the cohorts were from public databases, including Rizvi et al.’s discovery cohort after immune checkpoint inhibitor (ICI) treatment from the Memorial Sloan Kettering Cancer Center (MSKCC) database, the Pan-Lung Cancer cohort from the The Cancer Genome Atlas (TCGA) database, and non-small cell lung cancer (NSCLC) in the GSE41271 dataset for non-ICI treated patient data from the Gene Expression Omnibus (GEO) database; these data were based on Wistuba II’s sequencing and analysis of 275 lung cancer specimens collected from MD Anderson Cancer Center between 1997 and 2005, which mainly includes adenocarcinomas (n = 183) and squamous carcinomas (n = 80)
The clinical characteristics of MSKCC data discovery cohort and the TCGA and GEO cohorts are summarized in Supplementary Tables 2–4, while those of the mass cytometry (CyTOF) cohort are summarized in Supplementary Table 5
Summary
Lung cancer is one of the most frequently occurring types of tumor malignancy with the highest incidence worldwide. Immune checkpoint inhibitors (ICIs) are mainly used to treat programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA4) pathways. Multiple monoclonal anti-PD-1/PD-L1 monoclonal antibodies (mAbs) (including nivolumab, pembrolizumab, and atezolizumab) have been approved by the U.S Food and Drug Administration to treat advanced NSCLC, further confirming the importance of ICIs in the treatment of advanced NSCLC (Constantinidou et al, 2019; Lin et al, 2019). The emergence of immune checkpoint inhibitors (ICIs) has opened a new chapter for the treatment of non-small cell lung cancer (NSCLC), and the best beneficiaries of ICI treatment are still being explored. Smoking status has been repeatedly confirmed to affect the efficacy of ICIs in NSCLC patients, but the specific mechanism is still unclear
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