肿瘤炎性微环境中T细胞免疫调控前列腺癌神经内分泌分化的研究

Neuroendocrine prostate cancer (NEPC) is a subtype of prostate cancer with high malignancy and poor therapeutic effect. The changes in the tumor microenvironment can lead to neuroendocrine differentiation of prostate adenocarcinoma. However, the regulatory mechanism is still unclear. We found that the number of T cell that infiltration in tumor tissues of NEPC patients is lower than those prostate adenocarcinoma patients. Knockout P-selectin glycoprotein ligand-1 (PSGL-1), a cell adhesion molecule that expressed on leucocyte plasma membranes, in TRAMP spontaneous prostate cancer mice can decreased the number of T cell that infiltration in tumor tissues, and then the histologic characteristics of NEPC has emerged in tumor; therefore, we successfully established a novel model of spontaneous NEPC through changing the tumor inflammatory microenvironment (the model has been applied for patent). Furthermore, our work implies that T cell may play an important role in tumorigenesis of NEPC. Nevertheless, overexpression of CXCL1 is the key factor to drive transdifferentiation of prostate adenocarcinoma into neuroendocrine prostate cancer. In addition, TNF-α can up-regulate the expression of miR-200c and then further inhibition of CXCL1. Therefore, we presumed that the decrease of T cell that infiltration in tumor microenvironment could reduce the secretion of TNF-α, and then promote the expression of CXCL1, which could promote the differentiation of prostate adenocarcinoma into neuroendocrine prostate cancer. Following the scientific hypothesis, this project will clarify the function and immunoregulatory mechanism of T cell in the tumorigenesis of NEPC. Furthermore, studies on treatment of NEPC by targeting CXCL1 and a therapeutic method of NEPC using CXCL1 antibody will be carried out in this project.

前列腺神经内分泌癌(NEPC)是恶性程度高、治疗效果差的一个前列腺癌亚型。肿瘤微环境改变可导致前列腺腺癌向神经内分泌癌分化，但机制尚不清楚。我们发现NEPC患者肿瘤组织T细胞浸润数目低于腺癌患者；在自发前列腺癌TRAMP小鼠中敲除白细胞黏附分子PSGL-1后，肿瘤浸润T细胞数目降低，出现NEPC组织学特性，成功构建了炎性微环境改变诱发的NEPC小鼠模型(已申请专利)，并提示T细胞在NEPC发生中具有重要作用。进一步发现CXCL1高表达是驱动前列腺腺癌向神经内分泌癌分化的关键因子；TNF-α可上调miR-200c来抑制CXCL1表达。推测肿瘤T细胞浸润减少导致TNF-α分泌降低，进而上调癌细胞CXCL1，促进前列腺腺癌向神经内分泌癌分化。以此为科学假说，本项目将明确T细胞在NEPC发生中的作用并阐明其免疫调节机制，以CXCL1为靶点进行治疗研究，建立以CXCL1抗体为基础的NEPC治疗方法。

前列腺神经内分泌癌(NEPC)是恶性程度高、治疗效果差的一个前列腺癌亚型。迄今为止，免疫细胞对前列腺神经内分泌癌病理进程的影响尚不清楚。本项目主要研究肿瘤微环境中浸润的T细胞数目和功能的改变，及其对前列腺癌细胞向神经内分泌细胞分化的影响及调控机制。通过本项目的研究发现：1. NEPC患者肿瘤组织T细胞浸润数目和白细胞特异表达的黏附分子PSGL-1表达显著低于腺癌患者；2. 在自发前列腺癌TRAMP小鼠中敲除白细胞黏附分子PSGL-1后，肿瘤浸润T细胞数目降低，出现NEPC组织学特性，成功构建了炎性微环境改变诱发的NEPC小鼠模型(获得国家发明专利授权)，并提示T细胞在NEPC发生中具有重要作用。3. 通过提取C57和PSGL-1-/-小鼠CD4+和CD8+ T细胞并激活以及利用CD4+ Jurkat细胞，分别与PC3细胞共培养，仅CD4+ T细胞可以显著抑制PC3细胞神经内分泌标志物表达。4. 证实发现CXCL1高表达是驱动前列腺腺癌向神经内分泌癌分化的关键因子；并且利用CXCL1特异性抗体治疗TRAMP;PSGL-1-/-小鼠可以阻断前列腺癌的神经内分泌分化。5. 进一步发现T细胞分泌TNF-α降低可以抑制前列腺癌细胞miR-200c，进而上调癌细胞CXCL1，促进前列腺腺癌向神经内分泌癌分化。通过本项目的研究明确了CD4+ T细胞在NEPC发生中的作用并阐明其免疫调节机制，建立以CXCL1特异性抗体为基础的NEPC治疗方法，为临床NEPC靶向治疗提供了理论基础。