胰腺导管内乳头状黏液性肿瘤进展为浸润性癌过程中免疫景观的演变。
Evolution of the immune landscape during progression of pancreatic intraductal papillary mucinous neoplasms to invasive cancer.
机构信息
Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany.
Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany.
出版信息
EBioMedicine. 2020 Apr;54:102714. doi: 10.1016/j.ebiom.2020.102714. Epub 2020 Apr 4.
BACKGROUND
Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions of pancreatic cancer, which is characterized by an immunosuppressive microenvironment. Yet, the spatial distribution of the immune infiltrate and how it changes during IPMN progression is just beginning to be understood.
METHODS
We obtained tissue samples from patients who underwent pancreatic surgery for IPMN, and performed comprehensive immunohistochemical analyses to investigate the clinical significance, composition and spatial organization of the immune microenvironment during progression of IPMNs. Survival analysis of pancreatic cancer patients was stratified by tumour infiltrating immune cell subtypes.
FINDINGS
The immune microenvironment evolves from a diverse T cell mixture, comprising CD8 T cells, Th/c1 and Th/c2 as major players combined with Th9, Th/c17, Th22, and Treg cells in low-grade IPMN, to a Treg dominated immunosuppressive state in invasive pancreatic cancer. Organized lymphoid clusters formed in IPMN surrounding stroma and accumulated immunosuppressive cell types during tumour progression. Survival of pancreatic cancer patients correlated with Th2 signatures in the tumour microenvironment.
INTERPRETATION
The major change with regards to T cell composition during IPMN progression occurs at the step of tissue invasion, indicating that malignant transformation only occurs when tumour immune surveillance is overcome. This suggests that novel immunotherapies that would boost spontaneous antitumor immunity at premalignant states could prevent pancreatic cancer development.
FUNDING
The present work was supported by German Cancer Aid grants (70,112,720 and 70,113,167) to S. R., and the Olympia Morata Programme of the Medical Faculty of Heidelberg University to S. R.
背景
导管内乳头状黏液性肿瘤（IPMNs）是胰腺癌的前体病变，其特征为免疫抑制性微环境。然而，免疫浸润的空间分布及其在 IPMN 进展过程中的变化才刚刚开始被理解。
方法
我们从接受胰腺手术治疗 IPMN 的患者中获得组织样本，并进行全面的免疫组织化学分析，以研究 IPMN 进展过程中免疫微环境的临床意义、组成和空间组织。对胰腺癌患者进行生存分析，根据肿瘤浸润免疫细胞亚型进行分层。
结果
免疫微环境从富含 CD8 T 细胞、Th/c1 和 Th/c2 的多样化 T 细胞混合物演变为低级别 IPMN 中的 Treg 主导的免疫抑制状态，在侵袭性胰腺癌中则形成了组织浸润免疫细胞类型的有组织的淋巴簇。肿瘤进展过程中，IPMN 周围基质形成了有组织的淋巴簇，并积累了免疫抑制细胞类型。胰腺癌患者的生存与肿瘤微环境中的 Th2 特征相关。
解释
在 IPMN 进展过程中，T 细胞组成的主要变化发生在组织侵袭阶段，这表明只有当肿瘤免疫监视被克服时，恶性转化才会发生。这表明，在癌前状态下增强自发抗肿瘤免疫的新型免疫疗法可能预防胰腺癌的发生。
资助
本研究得到德国癌症援助基金（70,112,720 和 70,113,167）的支持（S.R.），以及海德堡大学医学院奥林匹亚·莫拉塔计划的支持（S.R.）。
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