Abstract 321P
Background
Patients with small cell lung cancer (SCLC) currently receive standard treatment of chemotherapy combined with immunotherapy, and there is a need to use accurate predictive biomarkers to identify immune-responsive patients. We have previously identified pathogenic germline variants in DNA damage response (DDR) genes linked to significantly prolonged responses to immunotherapy in lung cancer patients, suggesting potential novel biomarker applications. Here, we aimed to explore the role of stop-gain variants in DDR genes in impacting the transcriptomic profile of peripheral blood mononuclear cells (PBMCs) from SCLC patients and how they correlate with immuneactivation markers.
Methods
Extensive-stage SCLC patients receiving chemo-immunotherapy were enrolled and stratified into best responders (BR) and non-responders (NR). Patients-derived PBMCs were isolated by Ficoll method and subjected to next-generation sequencing (NGS, SmartSeq Sequencing Cancer Panels, MiSeq platform) and RNA sequencing.
Results
NGS analysis of PBMCs from BR patients identified pathogenic variants in the BARD1 (c.1216C>T), BRCA1 (c.5278-31C>T), and MSH2 (c.367-45A>G) genes. Additionally, missense variants in the POLE (c.1274A>G) and STK11 (c.397G>A) genes were detected. Correlation analysis of RNA-seq data demonstrated that the expression of germline variant-associated genes was linked to immune activation markers, specifically the expression of Stimulator of Interferon Genes (STING) and Mitochondrial Antiviral Signaling Protein (MAVS). Notably, BARD1 exhibited a negative correlation with STING (r=−0.93) and MAVS (r=−0.77), while POLE showed a positive correlation with MAVS (r=0.94). Furthermore, PDL1 was negatively correlated with STING (r=−0.85, p=0.03) and positively correlated with BARD1, BRCA1, and MSH2. Subsequently, the DDR score was calculated based on the Z-scores of FPKM values, revealing that NR patients exhibited higher DDR scores compared to BR patients.
Conclusions
BARD1/POLE germline variants in PBMCs of SCLC patients correlates with expression of immune activation markers, thus indicating that may help the identification of immune-responsive patients.
Legal entity responsible for the study
The authors.
Funding
AIRC.
Disclosure
All authors have declared no conflicts of interest.