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.
Poupault et al. (2026) studied this question.