Leveraging PMN immune response to overcome ADT resistance in bone metastatic prostate cancer

转移性去势抵抗性前列腺癌（mCRPC）是致命的，目前无法治愈。约90% 的CRPC患者对二线雄激素剥夺治疗（ADT;主要针对 雄激素受体（AR）信号传导并与骨转移性疾病相关。尽管ADT仍然是一种有益的 mCRPC患者的治疗，mCRPC中的癌症耐药机制，特别是骨中的癌症耐药机制 CRPC转移最常见的部位是环境，但对其了解甚少。理解贡献 需要进一步开发有效的治疗方法。adt是 先前显示对多形核白细胞/中性粒细胞的分化和功能至关重要 在一些实施方案中，骨髓基质细胞是中性粒细胞（PMNs），其是占骨髓腔的约40 - 50%的"第一应答者"先天免疫细胞。我们 最近表明，PMN对骨转移性前列腺癌（BM-PCa）具有保护作用，然而， 抗肿瘤免疫应答随着肿瘤进展而减弱。检查PMN表型变化 在PCa患者的整个进展过程中，我的小组在功能上和分子上表征了外周血 来自不同阶段的PCa患者的PMN：1）局限性PCa，2）骨转移瘤敏感性（mCSPC）， （3）mCRPC患者。我们发现，二线ADT通过增加PMN功能， 转化生长因子β（TGF β）受体1的表达，TGF β是一种重要的抗炎细胞因子， 促进BM-PCa和癌症引起的骨病。使用临床前骨转移小鼠模型，我们 使用二线ADT联合任一双极均能够显著抑制mCRPC在骨中的生长 雄激素治疗（BAT;外源性睾酮），以提高PMN抗肿瘤反应或PMN特异性遗传 T β R1缺失。基于我们的初步发现，我们假设：抗肿瘤的中性粒细胞被抑制， 雄激素通过T β R1信号调节"关闭"，这可用于改善mCRPC 结果。这将在以下目标中得到检验：目标1。确定雄激素调节对PMN的影响 抗肿瘤免疫应答。目标二。探讨T β R1介导的中性粒细胞免疫应答的机制。 BM-PCa。目标3：阐明T β R1/AR双重调节改善mCRPC的治疗潜力 治疗结果。主要目的：建立一种新的治疗骨髓瘤前列腺癌（BM-PCa）的免疫策略 通过增强PMN抗肿瘤反应和克服PCa对ADT的耐药性。研究设计：对于目标1， 我们将确定雄激素信号传导对离体PMN极化的影响（使用患者来源的PMN和 小鼠骨髓PMN）和体内使用正常PCa、非转移性和骨转移性PCa细胞），以及 体内（使用小鼠胫骨内骨转移模型）。对于目标2，我们将描述T β R1在PMN中的作用， 使用T β R1敲除模型对mCRPC的应答。对于目标3，我们将定义使用 BAT与新型骨靶向T β R1抑制剂的组合。

Metastatic castration-resistant prostate cancer (mCRPC) is deadly and currently incurable. Approximately 90% of patients CRPC become resistant to 2nd line androgen deprivation therapy (ADT; which primarily target androgen receptor (AR) signaling and present with bone metastatic disease. Although ADT remains a beneficial therapy for mCRPC patients, mechanisms of cancer resistance in mCRPC and specifically, in the bone environment, the most frequent site of CRPC metastasis, is poorly understood. Understanding contributing factors to PCa disease progression is needed for further development of efficacious therapies. ADT was previously shown to be critical for differentiation and function of polymorphonuclear leukocytes/neutrophils (PMNs) which are “first responder” innate immune cells that comprise ~40-50% of the bone marrow cavity. We recently showed that PMNs are protective against bone metastatic prostate cancer (BM-PCa) however, the PMN anti-tumoral immune response diminishes as the tumor progresses. To examine PMN phenotypical changes throughout PCa progression in patients, my group functionally and molecularly characterized peripheral blood PMNs from PCa patients at different stages: 1) Localized PCa, 2) bone metastatic hormone-sensitive (mCSPC), and 3) mCRPC patient. We found that PMN function was highly suppressed by 2nd line ADT through increased receptor 1 expression of transforming growth factor beta (TGFβ), an anti-inflammatory cytokine important for promoting BM-PCa and cancer-induced bone disease. Using preclinical bone metastasis mouse models, we were able to significantly suppress mCRPC growth in bone using 2nd line ADT in combination with either bipolar androgen therapy (BAT; exogenous testosterone) to boost PMN anti-tumor response OR PMN-specific genetic deletion of TβR1. Based on our preliminary findings, we hypothesize that: anti-tumor PMNs are suppressed/ “switched off” by androgen regulation via TβR1 signaling and this can be leveraged to improve mCRPC outcomes. This will be tested in the following aims: Aim 1. Define the impact of androgen regulation on PMN anti-tumor immune response. Aim 2. Determine the mechanism of TβR1-mediated PMN immune response in BM-PCa. Aim 3. Delineate the therapeutic potential of dual TβR1/AR regulation for improving mCRPC therapeutic outcomes. Primary Objective: To develop a novel immunotherapeutic strategy for treating BM-PCa by enhancing PMN anti-tumor response and overcoming PCa resistance to ADT. Study Design: For Aim 1, we will identify the impact of androgen signaling on PMN polarization ex vivo (using patient-derived PMNs and mouse bone marrow PMNs) and in vivo using normal PCa, non-metastatic and bone metastatic PCa cells) and in vivo (using mouse intratibial bone metastasis models). For Aim 2, we will delineate the role of TβR1 in PMN response to mCRPC using TβR1 knockout models. For Aim 3, we will define the therapeutic potential for using combination BAT with a novel bone-targeted TβR1 inhibitor.