炎症微环境通过β-catenin/CCL3通路抑制CD103+DC趋化并介导胰腺癌免疫逃逸的机制研究

Pancreatic cancer is characterized by poor prognosis and lacking of effective treatment. Investigation of mechanisms involved in the immune escape of pancreatic cancer may provide new targets for the treatment of this aggressive neoplasm. CD103 (αE) integrin expression distinguishes a population of dendritic cells (DCs). CD103+ DCs display distinctive functions such as cross-presentation of antigens in the draining lymph nodes, instruction of tissue-homing capacities on the activated T cells, and induction of regulatory T cells. CD103+ DCs play an important role in anti-tumor immunity. Recent studies revealed that activation of β-catenin pathway in melanoma repressed infiltration of CD103+ DCs, resulting in immune escape. With the support of our previous NSFC grants, we have proved that aberrant activation of β-catenin pathway in pancreatic cancer could be driven by inflammatory microenvironment, which was able to facilitate growth and metastasis of pancreatic cancer. Inflammatory microenvironment also repressed infiltration of CD103+ DCs. Furthermore, activated β-catenin pathway down-regulated expression of CCL3, a key cytokine participating in the chemotaxis of CD103+ DCs. All these investigations indicate that inflammatory microenvironment may be able to repress CD103+ DC infiltration through a β-catenin/CCL3 pathway dependent manner, leading to insufficient presentation of tumor antigens and immune escape of pancreatic cancer. By using several well-established animal models, various contemporary molecular biology techniques, and human pancreatic cancer specimens, we will verify the mechanisms involved in inflammation-driven immune escape of pancreatic cancer through β-catenin/CCL3/CD103+ DC pathway. Our study will not only establish a new paradigm that significantly affects our views on how chronic inflammation leads to the immune escape of pancreatic cancer, but will also lay groundwork for developing new therapeutic strategies against the deadly pancreatic cancer.

胰腺癌缺乏有效治疗手段,针对胰腺癌免疫逃逸机制的研究有望找到新靶点。CD103+树突状细胞(DC)浸润肿瘤组织是抗肿瘤免疫的关键。最近有研究发现,肿瘤中异常活化的β-catenin通路可抑制CD103+DC浸润,导致肿瘤免疫逃逸。课题组在前三个NSFC资助下证实:①炎症促进胰腺癌生长转移;②胰腺癌的炎症微环境能够激活β-catenin通路,并抑制CD103+DC的浸润;③β-catenin通路激活,可抑制CD103+DC趋化的关键细胞因子CCL3的表达。申请人推测炎症微环境很可能通过激活β-catenin通路抑制CCL3表达,进而抑制CD103+DC向胰腺癌组织浸润,削弱对肿瘤相关抗原的递呈,促进胰腺癌免疫逃逸。本研究将依靠前期建立的多种体外、体内模型,结合分子生物学手段和临床样本检测验证上述假设。本研究有助于阐明炎症微环境促进胰腺癌免疫逃逸的分子机制,为新治疗靶点的临床应用奠定理论基础。

胰腺癌预后极差，传统方法疗效不佳，急需寻找有效的治疗手段。肿瘤过继性细胞免疫治疗以其独特的优势越来越广泛地应用于肿瘤的临床治疗，但实体瘤的疗效不佳。本项目主要研究了胰腺癌中炎症/β-catenin/CCL3/CD103+DC信号转导机制对免疫逃逸及患者预后的影响。研究发现炎症能够影响胰腺癌细胞基因表达；能够激活胰腺癌细胞WNT/β-catenin信号通路；能够通过β-catenin/CCL3/CD103+DC信号转导机制促进胰腺癌细胞免疫逃逸；能够通过WNT/β-catenin通路促进BCL2L1、 BCL6、BID、BMP1、F11R和TGM2表达，影响胰腺癌患者预后；能够抑制胰腺癌化疗响应并通过WNT/β-catenin通路促进胰腺癌细胞迁移和上皮-间充质转化。基于本项目成果，研究过程中发现特定糖基转移酶可通过自催化作用锚定自身于DC表面并伴随肿瘤特异性抗原提呈给效应T细胞，研究者进一步鉴定并富集肿瘤微环境中肿瘤抗原特异性的肿瘤浸润T淋巴细胞，体外及体内实验均证实这一特定族群T细胞肿瘤细胞特异性杀伤作用极强，通过TCR-seq手段筛选识别肿瘤抗原的T细胞受体并建立TCR-T细胞系。该项目极大地优化了肿瘤个体化细胞免疫治疗，有望应用于实体肿瘤的临床治疗，改善广大肿瘤患者预后。共发表SCI论文15篇，培养硕士研究生3名，博士研究生1名，项目负责人赴美国斯克里普斯研究所进行学术交流，从事胰腺癌免疫治疗研究。