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

项目总结/摘要 免疫检查点疗法（ICT）已经彻底改变了几种恶性肿瘤的治疗， 甚至治愈一小部分癌症患者。然而，与高度反应性的肿瘤不同， 信息和通信技术（例如，黑色素瘤），大多数晚期前列腺癌患者对ICT反应较差， 在非选择性患者中已经观察到存活益处。尽管最近的临床前和临床研究 已经揭示了前列腺癌免疫抵抗的机制，细胞和分子的 前列腺癌中免疫耐药的基础仍不清楚。 骨髓源性抑制细胞（MDSC），一组病理活化的单核细胞， 具有有效免疫抑制活性的嗜中性粒细胞，已经被认为是免疫抑制的关键机制之一。 在各种疾病中，驱动肿瘤进展、转移和治疗抗性，包括对ICT的抗性， 癌的MDSC可分为多形核或粒细胞MDSC（PMN-MDSC或G-MDSC）。 或单核细胞MDSC（M-MDSC），其中PMN-MDSC是大多数癌症类型中的主要群体。我们 等已经证明PMN-MDSC是小鼠和人前列腺中主要的MDSC亚群 癌症，在前列腺癌进展和抗雄激素治疗耐药性中发挥重要作用， 信息和通信技术。相应地，治疗靶向MDSC延迟前列腺癌进展并改善前列腺癌的预后。 在临床前模型中对抗雄激素治疗和ICT的反应。重要的是，PMN-MDSC可能在临床上 它们与前列腺癌相关，因为它们大量存在于原发性和转移性肿瘤中。 新出现的证据表明，PMN-MDSC的代谢重编程在细胞凋亡中起重要作用。 它们的免疫抑制活性，但潜在的分子机制仍然不清楚。通过 多个数据集的转录组分析（单细胞RNA-seq，微阵列和批量RNA-seq），我们确定了 Acod 1编码顺式乌头酸脱羧酶（acod 1），是目前已知的在大肠杆菌中表达最高的代谢酶之一， 免疫抑制性PMN-MDSC中的基因。ACOD 1催化顺式-衣康酸酯的合成， 乌头酸在三羧酸（TCA）循环中，是一种新的免疫调节剂，具有强效抗炎和 在哺乳动物细胞中，特别是在巨噬细胞中的抗微生物作用。我们的结果出乎意料地显示， ACOD 1也可能是PMN-MDSC的潜在调节因子。我们假设ACOD 1促进肿瘤生长， 通过PMN-MDSC的代谢重编程在前列腺癌中对ICT的进展和抗性。我们将 在以下目标中测试我们的假设：目标1）。确定ACOD 1在调节 PMN-MDSC的免疫抑制活性。目标2）。确定ACOD 1在PMN-MDSC中的作用， 前列腺癌进展。目标3）。确定Acod 1 KO是否改善前列腺癌对以下药物的反应： 信息和通信技术。

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.