Abstract 6158: STING-MAVS interaction as novel immune mechanism of DNA-PK-inhibitor in SCLC

Abstract Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by significant replication stress and DNA damage. Recently an "inflamed" subset of SCLC has been identified, showing high expression of genes associated with Stimulator of Interferon Genes (STING)-induced T-cell attracting chemokines, such as CCL5 and CXCL10. The addition of DNA damage repair inhibitors (DDRis) to immunotherapy has been shown to enhance immune responses through STING-dependent activation pathways.This study focuses on the role of DNA-PK inhibition (DNA-PKi), a key regulator of DDR, in the activation of multiple cytosolic DNA/RNA sensors (STING, cGAS, MAVS, IFI16) to elucidate the molecular mechanisms linking DNA damage to immune responses.Treatment-naïve SCLC patients (n=10) and patients undergoing chemotherapy treatment (n=10) were enrolled. Blood samples were collected at baseline and after chemo-immunotherapy to analyze the expression of cGAS, STING, MAVS, and IFI16. Comprehensive transcriptomic analysis, real-time PCR and protein analysis were performed. STING, MAVS and cGAS knockdown and subcellular localisation analysis were also reported.SCLC tumor tissues (n=81) with higher STING-related chemokines (CCL5/CXCL10) exhibited increased expression of genes involved in MAVS pathway (IFITH1, DDX60), suggesting a simultaneous activation of STING and MAVS. DNA-PKi enhanced STING and MAVS more effectively than other DDRis in SCLC patients-derived PBMCs post-cisplatin compared to naïve patients, indicating its unique role in promoting immune responses. No significant changes in cGAS expression were observed in immune cells from SCLC patients, suggesting that the upregulation of STING mediated by DNA-PK inhibition is independent of cGAS, as knockdown of cGAS did not influence the upregulation of STING and p-IRF3 following DNA-PKi treatment. DNA-PKi treatment resulted in novel mitochondrial co-localization and physical interaction between STING and MAVS in PBMCs, leading to improved functional activation via nuclear translocation of p-IRF3.In conclusion, the study posits that DNA-PK inhibition facilitates a non-canonical interaction between STING and MAVS, thereby enhancing the innate immune response against SCLC. Citation Format: Caterina De Rosa, Luisa Amato, Concetta Tuccillo, Francesca Iommelli, Viviana De Rosa, Virginia Tirino, Federica Papaccio, Kavya Ramkumar, Qi Wang, Jing Wang, Alberto Servetto, Floriana Morgillo, Lauren Averett Byers, Fortunato Ciardiello, Carminia Maria Della Corte. STING-MAVS interaction as novel immune mechanism of DNA-PK-inhibitor in SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6158.