Association of IFITM3 with the efficacy of anti-PD1/PD-L1 therapy and regulation of immunosensitivity via MHC-I regulation in SCLC.

8105 Background: Majority of small cell lung cancer (SCLC) patients exhibit resistance to immune checkpoint inhibitors (ICIs), which is associated with the downregulation of major histocompatibility complex class I (MHC-I) molecules. This study investigates the regulatory mechanisms underlying MHC-I expression and explores potential therapeutic strategies to enhance ICI efficacy. Methods: Single-cell and bulk RNA sequencing data from SCLC patient tumors were analyzed to identify key regulators of MHC-I expression. The IMpower133 cohort (116 patients treated with chemotherapy plus anti-PD-L1 therapy and 131 patients treated with chemotherapy alone) and an in-house cohort (39 patients treated with chemotherapy and anti-PD-1 therapy) were utilized to assess the association between IFITM3 expression and immunotherapy outcomes. Additionally, tumor samples from 42 extensive-stage SCLC patients receiving first-line chemotherapy plus anti-PD1/PD-L1 were evaluated via immunohistochemistry (IHC) to determine IFITM3 expression as a predictive biomarker. In vitro and in vivo functional studies were conducted to elucidate the role and mechanisms of IFITM3 in modulating tumor sensitivity to PD-1 inhibitors. Results: Integrative analysis of multiple real-world cohorts of SCLC confirmed a significant positive association between IFITM3 and MHC-I expression. IFITM3 overexpression elevated MHC-I-related genes, activated antigen presentation pathways, and enhanced CD8 + T cell activity. In the IMpower133 cohort, high IFITM3 expression was significantly associated with prolonged progression-free survival (PFS) in patients receiving chemoimmunotherapy (HR 0.65,95% CI 0.44-0.96, p=0.014) but not in those treated with chemotherapy alone (HR 1.97,95%CI 1.19-3.25, p=0.0069). Similarly, in the in-house cohort, high IFITM3 expression conferred a PFS advantage in patients receiving chemoimmunotherapy (HR 0.42,95% CI 0.19-0.90, p=0.023). Furthermore, patients with elevated IFITM3 protein levels, as determined by IHC H-scores, exhibited improved clinical outcomes following chemoimmunotherapy. Importantly, inducing IFITM3 expression directly or through treatment with Ethyl gallate (EG), an IFITM3 activator, effectively sensitized tumors to PD-1 blockade in SCLC mouse models. Conclusions: IFITM3 positively regulates MHC-I expression and predicts response to ICIs in SCLC. Combining EG with PD-1 inhibitors represents a promising strategy to improve immunotherapy efficacy in SCLC patients.