胰腺癌发生发展过程中免疫微环境的动态分析提示免疫治疗的早期干预和联合策略。

Dynamic profiling of immune microenvironment during pancreatic cancer development suggests early intervention and combination strategy of immunotherapy.

机构信息

Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China.

出版信息

EBioMedicine. 2022 Apr;78:103958. doi: 10.1016/j.ebiom.2022.103958. Epub 2022 Mar 19.

DOI:10.1016/j.ebiom.2022.103958

PMID:35316682

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8943259/

Abstract

BACKGROUND

Pancreatic ductal adenocarcinoma (PDAC) has little response to immune checkpoint inhibitors. An in-depth understanding of the immune microenvironment from a comprehensive and dynamic perspective is critical to generate effective therapeutic strategies for PDAC.

METHODS

Using mass cytometry and immunohistochemistry, we explored the dynamic changes of tumor-infiltrating immune cells during the development of PDAC in a genetically engineered mouse model (Kras; Trp53; Pdx1-cre) and human specimens. PD-L1 mice were crossed with Kras; TgfβR2; Ptf1a-cre mice to achieve early depletion of PD-L1 in pancreatic cancer. Combination therapy of Arginase-1 (Arg-1) inhibitor and anti-PD-1 mAb was validated in syngeneic mouse models.

FINDINGS

Two different stages of immunosuppression with unique features were observed in both mouse model and human specimens. Early stage of immunosuppression featured highly abundant Tregs during acinar-to-ductal metaplasia, despite of a prominent and continuous presence of effector lymphocytes. The differentiation/activation branch of Ly-6C monocytes changed from a BST2/MHC-II phenotype to an Arg-1 phenotype over time during PDAC development. The late stage of immunosuppression thus featured the presence of a large number of myeloid suppressive cells together with a significant reduction of effector lymphocytes. Removal of PD-L1 from the beginning efficiently triggered anti-tumor immunity and significantly prolonged survival in PDAC-developing mice. Targeting Arg1 macrophages with an Arg-1 inhibitor synergized with anti-PD-1 immunotherapy and led to PDAC-specific immune memory.

INTERPRETATION

By demonstrating the coevolution of histopathology and immunology in PDAC, this study highlights the necessity and value of early intervention and combinational approach in leveraging immunotherapy to treat pancreatic cancer.

FUNDING

A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

摘要

背景

胰腺导管腺癌（PDAC）对免疫检查点抑制剂反应不佳。从全面和动态的角度深入了解肿瘤免疫微环境对于为 PDAC 生成有效的治疗策略至关重要。

方法

使用质谱流式细胞术和免疫组织化学，我们在遗传工程小鼠模型（Kras; Trp53; Pdx1-cre）和人类标本中探索了 PDAC 发展过程中肿瘤浸润免疫细胞的动态变化。将 PD-L1 小鼠与 Kras; TgfβR2; Ptf1a-cre 小鼠杂交，以实现胰腺癌中 PD-L1 的早期耗竭。在同基因小鼠模型中验证了精氨酸酶-1（Arg-1）抑制剂和抗 PD-1 mAb 的联合治疗。

发现

在小鼠模型和人类标本中都观察到了具有独特特征的两种不同的免疫抑制阶段。免疫抑制的早期阶段在腺泡到导管化生期间具有丰富的 Tregs，尽管效应淋巴细胞持续存在且数量众多。随着 PDAC 发展，Ly-6C 单核细胞的分化/激活分支从 BST2/MHC-II 表型转变为 Arg-1 表型。因此，免疫抑制的晚期阶段表现为大量髓系抑制细胞的存在，同时效应淋巴细胞数量显著减少。从一开始就去除 PD-L1 可有效地触发抗肿瘤免疫，并显著延长 PDAC 发展小鼠的存活时间。用 Arg-1 抑制剂靶向 Arg1 巨噬细胞与抗 PD-1 免疫疗法协同作用，并导致 PDAC 特异性免疫记忆。