34P Targeting LSD1 rescues MHC-I antigen presentation and overcomes resistance to PD-L1 checkpoint blockade in small cell lung cancer

Small cell lung cancer (SCLC) is a highly aggressive tumor with early primary resistance and modest clinical response to immune checkpoint blockade (ICB). Mutations or transcriptional repression of the major histocompatibility complex class I (MHC-I) represent key mechanism driving T cell-based therapies. Lysine-specific demethylase 1 (LSD1) regulates gene expression via demethylating lysines 4 9 histone H3 has been regarded as promising therapeutic target in SCLC. Here we investigated immunomodulatory functions LSD1 regulating MHC-I antigen presentation pathway (APP) immunotherapy To perturb function, employed pharmacological inhibitor ORY-1001 RNA interference assess changes SCLC lines by flow cytometry western blot. We then performed RNA-seq characterize whole transcriptomic cells following inhibition. explore effects targeting on cytolysis, co-cultured presenting endogenous peptides pre-activated cognate CD8+ cells. Finally, treated syngeneic immunocompetent mice bearing genetically engineered mouse model (GEMM)-derived tumors ORY1001 and/or anti-PD-L1 evaluate growth intratumor activities. discovered significant strong negative correlation between expressions KDM1A MHC-I/APP genes lines. demonstrated that restores surface expression, transcriptionally activates APP-regulatory genes, enhances immunogenic profile Perturbation interferon signaling, specifically activating transactivator functionally rescues MHC-I-restricted recognition cytolysis. Concurrent treatment sensitizes refractory models ICB antitumor CD8 Our data define potent regulator provide translational support for combinatory use inhibitors enhance sensitivity other MHC-I-deficient tumors.