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

转移性去势抵抗前列腺癌(MCRPC)是致命的，目前是无法治愈的。约90% CRPC患者对二线雄激素剥夺疗法(ADT；主要针对 雄激素受体(AR)信号转导和骨转移疾病的存在。尽管ADT仍然是一种有益的 MCRPC患者的治疗，mCRPC抗癌机制，特别是在骨中 环境是CRPC最常见的转移部位，但人们对此知之甚少。了解贡献 进一步开发有效的治疗方法需要影响PCa疾病进展的因素。ADT是 以前被证明对多形核白细胞/中性粒细胞的分化和功能至关重要 中性粒细胞(PMN)是一种“第一反应”的先天免疫细胞，约占骨髓腔的40-50%。我们 最近发现PMN对骨转移性前列腺癌(BM-PCa)有保护作用，而PMN 随着肿瘤的发展，抗肿瘤免疫反应减弱。检测PMN的表型变化 在整个前列腺癌患者的进展过程中，我的团队在功能和分子特征上表征了外周血 PCa患者不同阶段的PMN：1)局限性PCa，2)骨转移激素敏感(MCSPC)， (3)mCRPC患者。我们发现二线ADT通过增加PMN功能而高度抑制PMN功能 转化生长因子ββ受体1的表达 促进BM-PCA和癌症诱发的骨病。使用临床前骨转移小鼠模型，我们 我们能够显著抑制mCRPC在骨中的生长，使用二线ADT与任一双极相结合 雄激素治疗(BAT；外源性睾酮)增强PMN抗肿瘤反应或PMN特异性基因 删除TβR1。根据我们的初步发现，我们假设：抗肿瘤的PMN受到抑制。 通过TβR1信号被雄激素调节“关闭”，这可以用来改善mCRPC 结果。这将在以下目标中进行测试：目标1.确定雄激素调节对中性粒细胞的影响 抗肿瘤免疫反应。目的：探讨TβR1介导的小鼠多形核细胞免疫应答机制。 BM-PCA。目的3.阐明双TβR1/AR调节对改善mCRPC的治疗潜力 治疗效果。主要目的：建立治疗BM-PCa的新的免疫治疗策略 通过增强PMN的抗肿瘤反应，克服PCA对ADT的耐药性。研究设计：对于目标1， 我们将在体外确定雄激素信号对PMN极化的影响(使用患者来源的PMN和 小鼠骨髓中性粒细胞)和体内使用正常的PCA、非转移和骨转移的PCA细胞)和 体内(使用小鼠胫骨内骨转移模型)。对于目标2，我们将描述TβR1在中性粒细胞中的作用 使用TβR1基因敲除模型对mCRPC的响应。对于目标3，我们将定义使用 BAT与一种新型骨靶向TβR1抑制剂的联合应用。

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.