Thesis title: Studio sulle alterazioni del ritmo circadiano in pazienti affetti da cancro al polmone in stadio avanzato (NSCLC).
The circadian system represents a fundamental regulatory mechanism that orchestrates numerous physiological and molecular processes, including metabolism, cell proliferation, immune response, and hormonal secretion. Growing evidence indicates that circadian rhythm disruption significantly contributes to tumorigenesis, cancer progression, and interindividual variability in therapeutic response. In particular, in non-small cell lung cancer (NSCLC)—one of the leading causes of cancer-related mortality worldwide—the relationship between circadian dysregulation and modulation of the immune response remains poorly understood.
The aim of this doctoral study was to identify potential predictive factors associated with improved survival outcomes in patients with advanced-stage NSCLC treated with immune checkpoint inhibitors (ICIs), through an integrated analysis of circadian dysfunctions at both molecular and behavioral levels. The research was conducted on peripheral immune cells (PBMCs), representing an innovative and minimally invasive approach, as previous studies have primarily focused on tumor tissue or cells from the tumor microenvironment. This strategy enables the exploration of peripheral circadian biomarkers that may support clinical monitoring and therapeutic personalization.
The expression levels of the circadian genes CLOCK, TIMELESS, PER3, and PRF1 were analyzed in PBMCs obtained from 29 patients with NSCLC and 20 healthy controls. In parallel, circadian rhythms and sleep quality were evaluated using validated questionnaires: the Pittsburgh Sleep Quality Index (PSQI), the Composite Scale of Morningness (CSM), and the Circadian Type Inventory (CTI). The results revealed a significant overexpression of the investigated circadian genes in NSCLC patients compared with controls (p < 0.001). Notably, TIMELESS and PER3 were more highly expressed in patients with non-progressive disease, suggesting a possible prognostic value for these genes in predicting therapeutic response. Functionally, impaired sleep quality (PSQI > 5) was associated with increased levels of CD8+ T cells, CD14+ monocytes, and pro-inflammatory cytokines IL-14, IL-15, and TNFα, highlighting a close relationship between circadian disruption, systemic inflammation, and immune dysregulation.
Overall, the findings demonstrate that circadian dysregulation in NSCLC represents a systemic phenomenon involving peripheral immune components and is not restricted to the tumor microenvironment. Assessing circadian alterations in peripheral immune cells constitutes a promising avenue for the identification of non-invasive predictive biomarkers. Integrating circadian biology into cancer research provides new opportunities to enhance the understanding of tumor–immune interactions and to develop personalized chronotherapy strategies, ultimately improving therapeutic efficacy and quality of life in patients with non-small cell lung cancer.