Astha Patel
Research Mentor: Metin Cetin
Mentor Department: Department of Pathology, Medicine
Author(s): Metin Cetin, Navin Mahadevan, Max Kettles, Astha Patel
Session: Session 2 (10:00 AM – 10:50 AM)
Presentation Type: Poster 91
Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid metastatic spread, therapeutic resistance, and pronounced intratumoral plasticity. A major challenge in SCLC is the persistence of neuroendocrine (NE; ASCL1+ and NEUROD1+) tumor states that remain immune-cold despite the high mutational burden of this disease. These cells typically exhibit weak interferon signaling, poor antigen-presentation capacity, and limited chemokine production, supporting the idea that immune invisibility in SCLC is an actively maintained and therapeutically reversible phenotype. Our work focuses on using epigenetic inhibitors to reprogram NE SCLC toward a more immune-visible state and to create a foundation for effective innate immune activation. Our results broadly show that epigenetic priming can increase interferon responsiveness, enhance expression of antigen-presentation machinery, and promote immune-relevant signaling programs in SCLC models. These findings support a strategy in which chromatin-targeting agents are used not simply as cytotoxic drugs, but as immune-sensitizing tools that prepare tumors for combination treatment. The central therapeutic goal of this project is to combine epigenetic priming with the STING agonist ADU-S100 to maximize inflammatory signaling, chemokine induction, antigen presentation, and downstream T-cell engagement in advanced model systems. To address this, we integrate molecular characterization with functional immune readouts in three-dimensional microphysiological platforms. This framework allows us to test whether epigenetic reprogramming can potentiate ADU-S100-driven immune activation and overcome the immune-cold phenotype of NE SCLC. Overall, our findings support the concept that immune invisibility in SCLC is reversible and provide a rationale for mechanism-based combination therapies centered on ADU-S100. In future studies, we will extend this strategy by pairing epigenetic priming with metabolic vulnerability-directed approaches to more effectively target distinct SCLC cell states and limit therapeutic escape.
