Abstract 1772: A novel small molecule inhibitor, HO-4200, modulates macrophage polarization and suppresses MDSCs to enhance antitumor immune responses in ovarian cancer

Abstract Introduction: Ovarian cancer (OC) remains the deadliest gynecologic malignancy, with minimal improvement in the 5-year survival rate over the past three decades despite advancements in treatment. High-grade serous ovarian cancer (HGSOC) is characterized by aggressive progression, driven by elevated secretion of extracellular vesicles (EVs), tumor-associated macrophage (TAM) activation, and increased myeloid-derived suppressor cell (MDSC) populations. These factors contribute to immune suppression, metastasis, and poor patient outcomes. Here, we report on a novel small-molecule inhibitor, HO-4200, which modulates macrophage polarization and suppresses MDSCs within the ovarian tumor microenvironment. Methods: EV quantification and size characterization were performed using nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). In vivo studies using immunocompetent mice evaluated HO-4200's anticancer efficacy. Macrophage polarization and MDSC populations were analyzed via flow cytometry. The effects of HO-4200 on ovarian cancer and primary ascites-derived cell lines were examined in vitro. Additionally, expression levels of EV secretion pathway proteins TMEM205 and Rab27a were measured by ELISA and RT-PCR. Results: HO-4200 demonstrated significant antiproliferative effects, reducing ovarian cancer cell viability by 60-75% at concentrations of 2-5 µM after 48 hours. HO-4200 also inhibited the expression of EV secretion pathway proteins TMEM205 and Rab27a in ovarian cancer cells. Mechanistic studies revealed that HO-4200 promoted M1 macrophage polarization and reduced MDSC populations in vitro and in vivo immunocompetent mouse models. These findings suggest that HO-4200 suppresses EV secretion, thereby enhancing antitumor immune responses and reducing tumor progression and metastasis in ovarian cancer. Conclusion: This study provides the first evidence that HO-4200 inhibits ovarian cancer cell proliferation, promotes M1 macrophage polarization, and reduces MDSC populations by targeting EV secretion pathway proteins. These results highlight the therapeutic potential of HO-4200 in modulating the immune microenvironment and combating ovarian cancer progression and metastasis. Citation Format: Ganesh Yadaigiri, Kalpana Deepa Priya Dorayappan, Lakshmi Narasimhan Chakrapani, Shyam Sundaram, Jessica Velasquez, Casey Cosgrove, David M. O’Malley, David E. Cohn, Selvendiran Karuppaiyah. A novel small molecule inhibitor, HO-4200, modulates macrophage polarization and suppresses MDSCs to enhance antitumor immune responses in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1772.