Targeting LSD1 rescues MHC class I antigen presentation and promotes immune checkpoint blockade response in small cell lung cancer

Abstract

Abstract Purpose Small cell lung cancer (SCLC) is an aggressive tumor with modest clinical response to immune checkpoint blockade (ICB). Repression of major histocompatibility class I (MHC-I) molecules represents a key mechanism driving ICB resistance in SCLC. Recent studies have kindled interests in the lysine-specific demethylase 1 (LSD1) as an immunomodulatory target. Our study investigated the potential functions of LSD1 in regulating MHC-I antigen presentation in SCLC. Method We employed the inhibitor ORY-1001 and RNA interference to assess changes in MHC-I expression in SCLC cell lines by flow cytometry. We then performed RNA-seq to characterize whole transcriptomic changes in SCLC cells following LSD1 inhibition. To explore effects of targeting LSD1 on T cell cytolysis, we co-cultured SCLCs engineered to present endogenous peptides with pre-activated cognate CD8+ T cells. Finally, we treated immunocompetent mice bearing syngeneic SCLC tumors with ORY-1001 and/or anti-PD-L1 to evaluate tumor growth and characterize intratumor immune activities. Result We first demonstrated that targeting LSD1 restores MHC-I cell surface expression, transcriptionally activates APP-regulatory genes, and activates tumor intrinsic immunity. We further show that LSD1 inhibition of SCLC cells enables for efficient MHC-I-restricted T cell-mediated cytolysis. Finally, the addition of LSD1 inhibitor to anti-PD-L1 therapy significantly augments intratumor CD8+ T cell infiltrates and sensitizes refractory SCLC model to ICB response. Conclusion Our data define a potent regulatory role of LSD1 in MHC-I antigen presentation and provide support for targeting LSD1 to overcome immune evasion in SCLC. Supported by  NIH NCI R01 CA197936 (CMR); U24 CA213274 (CMR); the Druckenmiller Center for Lung Cancer Research (CMR, TS); NIH/NCI R01 CA258784 (TS); Congressionally Directed Medical Research Programs (DOD-IITRA) LC190161 (TS); Parker Institute for Cancer Immunotherapy grant (TS); LCFA-BMS/ILC Foundation Young Investigator Research Awards in Translational Immuno-oncology (TS); the Geoffrey Beene Foundation (EMN); The Yasuda Medical Foundation (HT); NIH K08 CA-248723 (AC); and the Van Andel Institute – Stand Up to Cancer Epigenetics Dream Team grant (CMR). Stand Up to Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. We also acknowledge the use of the MSKCC Flow Cytometry Core Facility, the MSKCC Antitumor Assessment Core, and the Integrated Genomics Core, which are funded by MSKCC Support Grant/Core Grant (P30 CA008748).