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

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

  • EBioMedicine. 2022 Apr;78:103958. doi: 10.1016/j.ebiom.2022.103958.
Jiaqi Yang 1,  Qi Zhang 2,  Junli Wang 1,  Yu Lou 1,  Zhengtao Hong 1,  Shumei Wei 3,  Ke Sun 4,  Jianing Wang 1,  Yiwen Chen 2,  Jianpeng Sheng 5,  Wei Su 2,  Xueli Bai 6,  Tingbo Liang 7
Affiliations

Affiliations

  • 1 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.
  • 2 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; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China.
  • 3 Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 4 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058 China; Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China.
  • 6 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; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058 China. Electronic address: shirleybai@zju.edu.cn.
  • 7 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; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058 China. Electronic address: liangtingbo@zju.edu.cn.
PMID: 35316682 DOI: 10.1016/j.ebiom.2022.103958
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 (KrasG12D/+; Trp53R172H/+; Pdx1-cre) and human specimens. PD-L1-/- mice were crossed with KrasG12D/+; TGFβR2flox/flox; 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.

Keywords

Immunotherapy; Mass cytometry; Pancreatic ductal adenocarcinoma; Tumor microenvironment; Tumor-infiltrating immune cells.

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