Purpose: Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare ovarian cancer of young women characterized by SWI/SNF ATPase SMARCA4 (BRG1) genetic inactivation alongside epigenetic silencing of the homolog ATPase SMARCA2 (BRM). Because the SWI/SNF complex associates with histone modifying complexes (HMCs) containing targetable epigenetic enzymes, the lack of SWI/SNF ATPase activity is hypothesized to interrupt normal function of HMCs that result in altered epigenetic landscape. Lysine-specific histone demethylase 1 (LSD1 or KDM1) regulates the chromatin landscape and gene expression by removing specific methyl groups from methylated proteins including histone H3. It associates with a number of transcriptional regulatory complexes including SWI/SNF and acts in a context-dependent manner. We and others have found that LSD1 is among the most highly expressed histone modifiers in SCCOHT. SCCOHT cell lines are very sensitive to the reversible LSD1 inhibitor SP-2509 compared to other epigenetic agents like EZH2 and bromodomain inhibitors, suggesting that LSD1 dependence is a defining feature of these SWI/SNF-deficient ovarian cancers. Recently it has been shown that LSD1 inhibition stimulates an INF-dependent anti-tumor immunity and overcomes resistance to checkpoint blockade through induction of Endogenous Retroviruses (ERVs) in breast cancer. Interestingly, SCCOHT have been shown to exhibit an immune-active tumor microenvironment with PD-L1 expression in both tumor and stromal cells that strongly correlated with T-cell infiltration (TIL). In this study we investigate the ability of SP-2509 to promote anti-tumor immunity and T-cell infiltration in SCCOHT.
Experimental Design: SCCOHT cell line BIN67, COV434 and SCCOHT1 were subjected to RT-PCR to evaluate ERVs induction and INF expression in response to SP-2509 treatment. SCCOHT cells were also co-cultured with peripheral blood mononuclear cells (PBMCs) in a 3D platform to evaluate T-cell infiltration following SP-2509 treatment.
Results: SP-2509 promotes ERV-mediated immune response in SCCOHT cell lines. Additionally, SP-2509 stimulates T-cell infiltration in SCCOHT in a spheroid platform.
Conclusion: Our data suggest that the reversible LSD1 inhibitor SP-2509 stimulates an INF-dependent anti-tumor immunity in SCCOHT cells in vitro and in 3D platform. Given that LSD-1 is a potential therapeutic target in SWI/SNF mutated SCCOHT, the combination of SP-2509 and PD-1 inhibitor represents a plausible combination to induce or augment immunogenic responses in these tumors.
Citation Format: Raffaella Soldi, Alexis Weston, Trason Thode, Rhonda Lewis, Mohan Kaadige, Hariprasad Vankayalapati, William Hendricks, Sunil Sharma. The reversible LSD1 inhibitor SP-2509 promotes anti-tumor immunity in small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3869.