Novel Regulators of Antigen Presentation and Therapeutic reactivation of MHC-I to overcome immune evasion in small cell lung cancer 2043

Description Background Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine cancer with dismal patient prognosis. SCLCs evade anti-tumor immunity by repressing major histocompatibility complex class I (MHC-I) expression and antigen presentation (AP). We performed a comprehensive analysis to identify regulators of MHC repression. Method Molecular profiling of 5056 NSCLCs and 944 SCLC tumors was performed using sequencing of DNA, RNA, and IHC. Single-cell transcriptomics of SCLC clinical samples and genetically engineered mouse models (GEMMs). Result We generated novel canonical (MHC-I/II) and non-canonical expression scores in SCLC clinical samples that measure the spectrum of AP repression across SCLC. The MHC-I score was correlated with RNA expression of key immune pathways (T cell, NK cell, and STING pathway) and was correlated with outcome to immunotherapy. CRISPR knockout studies identified non-homologous end-joining (NHEJ) gene, PRKDC (DNAPKCs) as a negative regulator of MHC-I. DNAPKCs inhibition significantly upregulated the expression of HLA-A/B/C, TAP1, and TAP2, and augmented the anti-tumor immune response of PD-L1 blockade in multiple GEMMs. Conclusion We established the heterogeneity of MHC repression across SCLC tumors and identified networks and pathways that can be targeted to de-repress MHC-I in SCLC. We established DNAPKCs as a therapeutic target that can augment the anti-tumor immune response of PD-L1 blockade by induction of MHC-I expression in SCLC. Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)