Cis-aconitate decarboxylase (ACOD1) in PMN-MDSC and prostate cancer progression

PROJECT SUMMARY/ABSTRACT Immune checkpoint therapy (ICT) has revolutionized the care of several malignancies, resulting in durable response and even cure in a small subset of cancer patients. However, unlike tumors that are highly responsive to ICT (e.g., melanoma), the majority of patients with advanced prostate cancer respond poorly to ICT and no survival benefits have been observed in non-selective patients. Although recent preclinical and clinical studies have shed some light on the mechanisms of immunoresistance in prostate cancer, the cellular and molecular basis of immunoresistance in prostate cancer remains poorly characterized. Myeloid-derived suppressor cells (MDSCs), a group of pathologically activated monocytes and neutrophils with potent immunosuppressive activities, have been implicated as one of the key mechanisms in driving tumor progression, metastasis, and therapeutic resistance, including resistance to ICT, in various cancers. MDSCs can be classified as polymorphonuclear or granulocytic MDSCs (PMN-MDSCs or G-MDSCs) or monocytic MDSCs (M-MDSCs), with PMN-MDSCs as the predominant population in most cancer types. We and others have demonstrated that PMN-MDSCs are the major MDSC subset in mouse and human prostate cancers, playing an important role in prostate cancer progression and resistance to anti-androgen therapy and ICT. Correspondingly, therapeutically targeting MDSCs delays prostate cancer progression and improves responses to anti-androgen therapy and ICT in preclinical models. Importantly, PMN-MDSCs may be clinically relevant to prostate cancer, as they are abundantly present in both primary and metastatic tumors. Emerging evidence suggests that metabolic reprogramming of PMN-MDSCs plays an important role in their immunosuppressive activities, yet the underlying molecular mechanisms are still poorly defined. Through transcriptome analyses (single-cell RNA-seq, microarray, and bulk RNA-seq) of multiple datasets, we identified Acod1, which encodes cis-aconitate decarboxylase (ACOD1), as one of the most highly expressed metabolic genes in immunosuppressive PMN-MDSCs. ACOD1, which catalyzes the synthesis of itaconate from cis- aconitate in the tricarboxylic acid (TCA) cycle, is a novel immunomodulator with potent anti-inflammatory and antimicrobial effects in mammalian cells, especially in macrophages. Our results unexpectedly showed that ACOD1 may also be a potential regulator of PMN-MDSCs. We hypothesize that ACOD1 promotes tumor progression and resistance to ICT in prostate cancer through metabolic reprogramming of PMN-MDSCs. We will test our hypothesis in the following aims: Aim 1). Determine the role of ACOD1 in regulating the immunosuppressive activities of PMN-MDSCs. Aim 2). Determine the role of ACOD1 in PMN-MDSCs in driving prostate cancer progression. Aim 3). Determine whether Acod1 KO improves the response of prostate cancer to ICT.