Abstract 1803: ACOD1 is a key regulator of immunosuppressive MDSCs, prostate cancer progression, and resistance to immunotherapy

Abstract

Abstract Although Immune checkpoint therapy (ICT) is highly effective in a wide range of malignancies, patients with metastatic castration-resistant prostate cancer (mCRPC) are largely resistant to ICT. Yet, the cellular and molecular basis of the poor response to ICT in lethal prostate cancer remain poorly defined. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) have emerged as a key driver of prostate cancer progression and resistance to immunotherapy. Yet the molecular mechanisms underlying the immunosuppressive activities of PMN-MDSCs remains poorly defined. By performing single-cell RNA-sequencing (scRNA-seq) of prostate tumors, we identified Acod1, a gene that encodes cis-aconitate decarboxylase (ACOD1) and catalyzes the synthesis of itaconate from cis-aconitate in the tricarboxylic acid (TCA) cycle, is among the top 5 metabolic-related genes that are overexpressed in PMN-MDSCs. Moreover, bulk RNA-seq and microarray datasets revealed that intratumoral and splenic PMN-MDSCs express a significantly higher level of Acod1 compared to less immunosuppressive bone marrow PMN-MDSCs. Importantly, high ACOD1 expression is strongly associated with significantly shorter overall survival and higher Gleason scores in human mCRPC. Using an autochthonous whole-body Acod1-KO mouse model, we showed that Acod1 KO in TRAMP mice led to a reduction in tumor burden and an increase in overall survival. Furthermore, using syngeneic prostate cancer models, we showed that whole-body or PMN-specific Acod1-KO delayed tumor progression. As expected, Acod1 KO dramatically reduced the production of itaconate in bone marrow-derived MDSCs (BM-MDSC) as shown by targeted metabolic profiling. Importantly, we found that Acod1 KO impaired immunosuppressive activities of BM-MDSC and an increase in CD3+ and CD8+ T cell infiltration in the tumors. Also, Acod1-KO in BM-MDSC led to a reduction of H2DCFDA staining intensity suggesting a reduction in the production of reactive oxygen species (ROS). Gene set enrichment analysis (GSEA) revealed that Acod1-KO MDSCs have hyperactive oxidative phosphorylation (OXPHOS) compared to Acod1-WT BM-MDSCs. KO of Acod1 also leads to suppression of key MDSC functions signaling such as TNFα/NFκB, IL6/JAK/STAT3, and C/EBPβ pathways. In summary, our data suggests that the upregulation of ACOD1 in PMN-MDSCs has a vital role in prostate cancer progression and resistance to ICT by regulating their immunosuppressive activities through metabolic reprogramming. Also, our data suggest that targeting ACOD1 could be an effective therapeutic strategy for lethal prostate cancer as a monotherapy and in combination with immunotherapy. Citation Format: Celia Sze Ling Mak, Xin Liang, Jessica Suh, Derek Liang, Ming Zhu, Guocan Wang. ACOD1 is a key regulator of immunosuppressive MDSCs, prostate cancer progression, and resistance to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1803.