Abstract A030: Reprogramming the SCLC tumor microenvironment to enhance immunotherapy response

Abstract Small cell lung cancer (SCLC) is an aggressive, poorly immunogenic, neuroendocrine cancer. Responses to the standard of care treatment (i.e., chemoradiation combined with anti-PD-(L)1 therapy) are often short-lived, and there is a need for novel strategies to enhance immunotherapy efficacy in SCLC patients. SCLC tumors are thought to be largely resistant to immunotherapy because of their immune-cold tumor microenvironment (TME), with few infiltrating T cells and low MHC-I expression in cancer cells. One notable exception is a small (∼15%) subtype of ‘inflamed’ tumors (SCLC-I), characterized by increased antigen presentation, interferon gamma (IFN-γ) signaling, and CD8+ T cell infiltration. SCLC-I tumors are associated with better responses to immunotherapy. Tumors in the SCLC-I subtype do not appear to be genetically distinct from other SCLC tumors, suggesting that it may be possible to reprogram the 85% of cold tumors into a more inflamed state that is more responsive to immunotherapies. Based on these observations, we hypothesize that treatment with specific cytokines may help “kick-start” local inflammation and activate anti-tumor immune responses. We will present data supporting this idea using IFN-γ, a pleiotropic cytokine that upregulates antigen presentation and activates and recruits immune cells. We first characterized the molecular effects of IFN-γ treatment in cell lines and in subcutaneous tumor models of immune-cold, neuroendocrine SCLC. Our data demonstrate that various murine in vitro and in vivo models of SCLC respond to IFN-γ treatment, resulting in reduced cell population growth and tumor growth inhibition, and increased MHC-I and PD-L1 expression. We also observed increased NK cells in these tumors at an early time point post-IFN-γ treatment. In vitro, co-culture of OT-I T cells with OVA-pulsed, IFN-γ pre-treated SCLC cells resulted in cancer cell death. Given these results, we next surmised that IFN-γ could synergize with anti-PD1 therapy to slow subcutaneous tumor growth. Interestingly, there was no benefit of the combination therapy compared to IFN-γ alone. We are currently investigating this unexpected finding to identify the mechanism of immune evasion in these tumors. In conclusion, our work demonstrates that while murine neuroendocrine SCLC models respond to IFN-γ treatment in vitro and in vivo and can be killed by T cells in vitro when their cognate antigen is present, surprisingly, IFN-γ treatment does not synergize with anti-PD1 in these models. We are currently investigating the kinetics of the IFN-γ response in vivo and exploring the impact of treatment on the TME. IFN-γ and other cytokines may provide simple means to enhance the anti-tumor effects of immunotherapies in patients with cold tumors. Citation Format: Clara Poupault, Julien Sage. Reprogramming the SCLC tumor microenvironment to enhance immunotherapy response [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A030.