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

Background

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 a key mechanism driving resistance to T cell-based therapies. Lysine-specific demethylase 1 (LSD1) regulates gene expression via demethylating lysines 4 and 9 of histone H3 and has been regarded as a promising therapeutic target in SCLC. Here we investigated the immunomodulatory functions of LSD1 in regulating MHC-I antigen presentation pathway (APP) and resistance to immunotherapy in SCLC.

Methods

To perturb LSD1 function, we employed the pharmacological inhibitor ORY-1001 and RNA interference to assess changes in MHC-I expression in SCLC cell lines by flow cytometry and western blot. 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 SCLC presenting endogenous peptides with pre-activated primary cognate CD8+ T cells. Finally, we treated syngeneic immunocompetent mice bearing genetically engineered mouse model (GEMM)-derived tumors with ORY1001 and/or anti-PD-L1 to evaluate tumor growth and characterize intratumor immune activities.

Results

We discovered a significant and strong negative correlation between expressions of KDM1A and MHC-I/APP genes in SCLC cell lines. We then demonstrated that targeting LSD1 restores MHC-I cell surface expression, transcriptionally activates APP-regulatory genes, and enhances the immunogenic profile of SCLC. Perturbation of LSD1 activates interferon signaling, specifically activating a transactivator of MHC-I genes, and functionally rescues MHC-I-restricted T cell recognition and cytolysis. Concurrent treatment of LSD1 inhibitor and anti-PD-L1 sensitizes refractory SCLC models to ICB via antitumor CD8 T cell activities.

Conclusions

Our data define LSD1 as a potent regulator of antigen presentation in the tumor and provide translational support for combinatory use of LSD1 inhibitors to enhance ICB sensitivity in SCLC and other MHC-I-deficient tumors.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

T. Sen: Financial Interests, Personal, Research Grant: Jazz Therapeutics. C.M. Rudin: Financial Interests, Personal, Advisory Board: Bridge Medicines, Earli, Harpoon Therapeutics. All other authors have declared no conflicts of interest.