Exploring the Complex Interplay between Myeloid-Derived Suppressor Cells (MDSCs), Interleukins, and Immune Checkpoint Inhibitors (ICIs) in Non-Small Cell Lung Cancer (NSCLC)

In the era of immunotherapy, exploring the interplay between immune checkpoint inhibitor (ICI) therapy and myeloid-derived suppressor cells (MDSCs), as well as Interleukins, in non-small cell lung cancer (NSCLC) appears intriguing. The first prospective part of this thesis investigates the impact of ICI therapy on the immunological landscape and the expression of cellular FLICE (FADD-like interleukin-1β-converting enzyme)-inhibitory protein (c-FLIP) in MDSCs. Thirtyfour NSCLC patients were longitudinally analyzed, revealing a reduction in proinflammatory cytokines exclusively in non-progressors (NP) after ICI treatment. Through advanced analysis techniques, a distinctive decrease in c-FLIP expression in monocytic (M)-MDSCs from NP patients was identified, suggesting a potential role of ICI therapy in mitigating systemic inflammation and impairing MDSC-dependent immunosuppression. The second study, a comprehensive meta-analysis, focuses on the prognostic role of IL-8 in lung cancer in patients undergoing different treatment approaches (immunotherapy, chemotherapy, surgery, or tyrosine kinase inhibitors). Thirteen studies encompassing different lung cancer stages were included in the analysis. High levels of IL-8 were associated with a significantly shorter overall survival (OS) in patients, particularly those treated with immunotherapy. Moreover, through OS analysis using RNA-seq data from The Cancer Genome Atlas (TCGA), the high expression of IL8 in patients with lung cancer was associated with worse OS than patients with low IL8 expression. By merging the insights from these two analyses, this thesis provides a comprehensive understanding of the intricate relationship between ICI therapy, the immunological landscape, and the prognostic impact of IL-8 in NSCLC. The findings suggest that ICI therapy can modulate the immune response, reducing systemic inflammation and impairing MDSC-dependent immunosuppression. Moreover, the meta-analysis underscores the negative prognostic impact of high IL-8 levels, particularly in patients treated with immunotherapy, highlighting the potential clinical implications of these findings in the management of lung cancer.