Unveiling drivers of MHC repression and therapeutic strategies to counter immune evasion in small cell lung cancer.

8091 Background: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with a median survival of 9–11 months. Despite the addition of immune checkpoint blockade (ICB) to frontline chemotherapy, improvements remain limited. SCLC evades anti-tumor immunity by suppressing major histocompatibility complex class I (MHC-I) and antigen presentation (AP). The variability of MHC repression across molecular subtypes of SCLC and high-grade neuroendocrine tumors is not fully understood. This study analyzed clinical SCLC and neuroendocrine tumor samples to identify molecular subtypes and regulators of MHC repression, enhancing the understanding of immune evasion. Methods: Molecular profiling was conducted on 944 SCLC and 5056 non-small cell lung cancer (NSCLC) tumors using next-generation DNA (592-gene panel/whole exome), RNA (whole transcriptome) sequencing, and immunohistochemistry. Transcriptomic profiling of 40 SCLC cell lines and genetically engineered mouse models (GEMMs) was also performed. Results: Key regulators and gene networks driving MHC-I suppression in SCLC and other high-grade neuroendocrine tumors were identified. Canonical (MHC-I and II) and non-canonical AP expression scores characterized the spectrum of MHC-I repression across subtypes. Low MHC-I scores correlated with reduced immune signatures (e.g., T cell-inflamed, NK cell, and STING pathway signatures; Spearman = 0.87, 0.58, 0.62, respectively) and predicted poor OS and PFS to immunotherapy. Enhancer network and gene expression analyses identified actionable regulators of MHC-I repression, including interferon signaling. Knockout studies of top MHC-I regulators and single cell analyses revealed non-homologous end-joining (NHEJ) genes (like DNAPKCs) inversely correlated with HLA-A/B/C expression. DNAPKCs inhibition upregulated MHC-I, TAP1, and TAP2, enhanced antigen-specific T-cell-mediated cytolysis in SCLC. This inhibition activated the STING pathway, increased CD8+ T-cell infiltration, and enhanced MHC Class-I. Combining DNAPKCs inhibitor NU1774 with anti-PD-L1 reactivated MHC-I and led to significant tumor regression in aggressive murine SCLC models, supporting new combination therapies. Conclusions: We identified molecular subtypes and actionable pathways to restore MHC-I expression in SCLC, advancing understanding of immune evasion mechanisms. DNAPKCs is established as a key therapeutic target, enhancing PD-L1 blockade by reactivating antigen presentation. The developed MHC-I expression scores and associated biomarkers offer predictive tools for identifying patients likely to benefit from immunotherapy. These findings support biomarker-driven, personalized approaches to improve treatment for SCLC, addressing a critical unmet need in this devastating cancer.