新型MDSC亚群介导的免疫微环境在胰腺癌神经浸润中的病理机制研究

Pancreatic ductal adenocarcinoma (PDAC) is one of the highest malignancy in the digestive system tumor, the prognosis of this tumor is poor and there are not valid therapy available. The key factor of itspoor prognosis is the high occurence rate of invasion and metastasis. Especially the perineural invasion (PNI) of PDAC is up to 80~100%, which is the pathological basis of recurrence and metastasis of PDAC, but the molecular mechanism is far from clear. PDAC has a special interstitial - immune microenvironment, Preliminary studies indicated that there is existence of a large number of FAP-α+ activation of fibroblast in tumor stroma and FAP-α and SDF-1 is high expression in PDAC tumor cells. We found that there is a new MDSC subset which has high expression of CD13 play a important role of immune suppression. Preliminary results suggest that MDSC may be involved in the progression of PDAC in PNI. During the study, we will use dorsal root ganglion - tumor cells co-culture model and mice nerve infiltration in vivo model .In order to study the relationship between interstitial - immune microenvironment mediated by FAP- alpha fibroblasts and CD13hiMDSC with PNI, to investigate the FAP- alpha /SDF-1 pathway involved in immune escape mediated by CD13hiMDSC, to investigate the role of CD13hi MDSC participate in the progression of PNI. And we desire to provide the experimental basis for the clinical comprehensive treatment for PNI of PDAC.

胰腺导管腺癌（PDAC）是消化系统恶性程度最高的肿瘤之一，缺乏理想治疗方案，预后极差，关键因素为其高复发和高转移率，特别是周围神经浸润（PNI）高达80~100%，是PDAC复发和转移的病理学基础，但分子机制远未明确。前期研究发现PDAC存在特殊的间质—免疫微环境，肿瘤间质中存在大量FAP-α+活化的纤维母细胞，且胰腺癌细胞也表达FAP-α和SDF-1，在PDAC中发现一群发挥免疫抑制作用的高表达CD13的髓源性抑制细胞（CD13hiMDSC）。初步结果提示MDSC可能参与了PDAC中PNI的进展。本课题拟采用背根神经节肿瘤细胞共培养和小鼠体内神经浸润模型，研究活化纤维母细胞和CD13hiMDSC介导的间质-免疫微环境与PNI的关系，探讨FAP-α/SDF-1途径是否参与CD13hiMDSC介导的免疫逃逸，明确CD13hiMDSC参与PNI的作用，为针对PNI的临床综合治疗提供实验基础。

胰腺导管腺癌（PDAC）是消化系统恶性程度最高的肿瘤之一，缺乏理想治疗方案，预后极差，关键因素为其高复发和高转移率，特别是周围神经浸润（PNI）高达80-100%，是PDAC复发和转移的病理学基础，但分子机制远未明确。前期研究发现，在胰腺癌癌旁组织和慢性胰腺炎中神经周围存在淋巴单核样细胞围绕的淋巴单核样细胞套，但在胰腺癌肿瘤神经浸润发生时，淋巴单核样细胞会完全消失，这一现象提示胰腺癌的免疫细胞和神经浸润存在密切的关系。.本课题通过对两百例胰腺癌和慢性胰腺炎组织病理切片的观察和免疫组化标记，对胰腺癌肿瘤组织、癌旁组织和慢性胰腺炎微环境进行了全面的对比和评价。研究发现慢性胰腺炎和胰腺癌癌旁组织具有相似的微环境，提示慢性炎在胰腺癌中提供了利于肿瘤发展的微环境，慢性纤维包块型胰腺炎FMCP可能为PDAC的癌前病变,重视FMCP的诊断和治疗对PDAC的预防具有极为重要的意义。同时，基于胰腺癌复杂的肿瘤免疫微环境，在胰腺癌患者外周血中发现了两群MDSC新亚群，CD13hiMDSCs和CD13low MDSCs，并对胰腺导管腺癌中MDSC新亚群进行分型、鉴定和功能研究，运用MDSC新亚群对胰腺癌患者预后进行了评估判断，提示MDSC新亚群可能做为一种新型的预后的标志物，为胰腺癌患者未来的预后和复发、转移提供了新方向。另外，对胰腺癌肿瘤相关间质细胞和这两群MDSC新亚群的关系进行了初步研究，有望为胰腺癌免疫治疗和胰腺癌神经浸润的靶向治疗开启新方向。