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
  • 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: [email protected].
  • 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: [email protected].
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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