灭活免疫抑制骨髓性细胞从而增强前列腺癌的免疫疗法

Tumor immunotherapy, especially immune checkpoint blockade (ICB) antibodies, represents a promising therapeutic approach to achieve durable response in prostate cancer patients, but one limiting factors is the immunosuppressive cells in the context of lethal metastatic castration-resistant prostate cancer (mCRPC). In our recent studies, we showed that myeloid derived suppressor cells (MDSC) play a crucial role in mediating tumor immune evasion and promoting tumor progression in a transgenic mouse model of aggressive prostate cancer. Recruitment and activation of MDSC is driven by a YAP/CXCL5/CXCR2 signaling pathway. Importantly, drugs that effectively inactivate MDSC such as cabozantinib and BEZ235 synergize dramatically with ICB agents anti-CTLA4 and anti-PD1 antibodies to impair primary CRPC. However, it is unclear whether MDSC, and/or tumor-associated macrophage (TAM) play a similarly important role in metastatic CRPC, including metastasis to bone and to lung. In this proposal, we propose to study the immunosuppressive function of MDSC and TAM in lung and bone metastatic CRPC in the Pten/p53/Smad4 syngeneic mouse model, and examine if extinguishing MDSC or TAM with small compound drugs can generate potent anti-metastasis effect when combined with ICB. For clinical validation, we will characterize various immune subpopulations in prostate tumors and validate the expression pattern and prognostic significance of YAP, CXCL5, CXCR2, and phospho-STAT3. Furthermore, we will compare MDSC and T cell infiltration between primary prostate tumor and bone metastasis, in order to determine if unique immune cell infiltration pattern is present in bone metastasis and requires distinct targeting strategy.

肿瘤免疫疗法，特别是免疫检查点阻断类抗体药物（ICB），可能为前列腺癌患者带来长期疗效，但免疫抑制细胞可能严重减弱免疫治疗对致死性的转移去势抗性前列腺癌（mCRPC）的疗效。我们的近期工作揭示了在前列腺癌的小鼠模型中，骨髓衍生抑制细胞（MDSC）对诱导免疫耐受起关键作用，抑制MDSC可以有效结合ICB对前列腺癌原发灶产生协同疗效。但MDSC或者同源系的肿瘤相关巨噬细胞（TAM）是否也在骨转移和肺转移CRPC中有类似功能还不清楚。我们提出在小鼠模型中研究MDSC和TAM在mCPRC中抑制T细胞免疫的功能，揭示抑制MDSC和TAM是否可以协同增强ICB免疫疗法对mCRPC的疗效；通过临床样品，验证YAP/CXCL5/CXCR2和STAT3信号通路在募集与激活MDSC中的作用，并且比较原位瘤与骨转瘤的免疫细胞侵入的关系。

具有多形核形态的髓源性抑制细胞 (PMN-MDSCs) 有助于前列腺癌的发生发展和免疫逃避。然而，肿瘤浸润性 PMN-MDSC 在原发性和转移性前列腺癌中的空间分布研究很少，特别是在比较肿瘤的上皮和间质隔室之间的情况下，尚无文章发表。在这项研究中，我们使用多色免疫荧光染色方法对 90 个原发性肿瘤、37 个淋巴结转移（均具有匹配的原发性肿瘤）和 35 个骨转移灶的存档样本进行了研究。 CD11b和 CD15双阳性的 细胞被鉴定为 PMN-MDSC，泛细胞角蛋白阳性的细胞被鉴定为前列腺上皮细胞。我们发现，在原发性肿瘤和转移灶中，相比起肿瘤区域的上皮区域，PMN-MDSCs 更容易浸润基质区域。与原发性肿瘤的基质区域相比，淋巴结转移或骨转移的基质区域被更多的 PMN-MDSCs 浸润。在原发性肿瘤中，间质 PMN-MDSC 与血管化、分段中性粒细胞、患者年龄和与肿瘤上皮细胞紧密并列有关。这些结果揭示了在前列腺癌组织中，基质而不是上皮细胞区域是 PMN-MDSCs 的主要温床，间接佐证了 PMN-MDSCs 在前列腺癌转移进展中的作用，进而支持当前作为抗癌新手段的抑制PMN-MDSCs的研究。

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