2. Academic Validation
  3. Transcriptional control of pancreatic cancer immunosuppression by metabolic enzyme CD73 in a tumor-autonomous and -autocrine manner

Transcriptional control of pancreatic cancer immunosuppression by metabolic enzyme CD73 in a tumor-autonomous and -autocrine manner

  • Nat Commun. 2023 Jun 8;14(1):3364. doi: 10.1038/s41467-023-38578-3.
Tianyu Tang # 1 2 3 4 5,  Xing Huang # 6 7 8 9 10,  Minghao Lu # 1 2 3 4 5,  Gang Zhang 1 2 3 4 5,  Xu Han 1 2 3 4 5,  Tingbo Liang 11 12 13 14 15
Affiliations

Affiliations

  • 1 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang, China.
  • 2 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China.
  • 3 Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, 310003, Hangzhou, Zhejiang, China.
  • 4 The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, 310009, Hangzhou, Zhejiang, China.
  • 5 Cancer Center, Zhejiang University, 310058, Hangzhou, Zhejiang, China.
  • 6 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang, China. huangxing66@zju.edu.cn.
  • 7 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China. huangxing66@zju.edu.cn.
  • 8 Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, 310003, Hangzhou, Zhejiang, China. huangxing66@zju.edu.cn.
  • 9 The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, 310009, Hangzhou, Zhejiang, China. huangxing66@zju.edu.cn.
  • 10 Cancer Center, Zhejiang University, 310058, Hangzhou, Zhejiang, China. huangxing66@zju.edu.cn.
  • 11 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang, China. liangtingbo@zju.edu.cn.
  • 12 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China. liangtingbo@zju.edu.cn.
  • 13 Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, 310003, Hangzhou, Zhejiang, China. liangtingbo@zju.edu.cn.
  • 14 The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, 310009, Hangzhou, Zhejiang, China. liangtingbo@zju.edu.cn.
  • 15 Cancer Center, Zhejiang University, 310058, Hangzhou, Zhejiang, China. liangtingbo@zju.edu.cn.
  • # Contributed equally.
PMID: 37291128 DOI: 10.1038/s41467-023-38578-3
Abstract

Cancer cell metabolism contributes to the establishment of an immunosuppressive tumor microenvironment. Aberrant expression of CD73, a critical Enzyme in ATP metabolism, on the cell surface results in the extracellular accumulation of adenosine, which exhibits direct inhibitory effects on tumor-infiltrating lymphocytes. However, little is known about the influence of CD73 on negative immune regulation-associated signaling molecules and transduction pathways inside tumor cells. This study aims to demonstrate the moonlighting functions of CD73 in immunosuppression in pancreatic Cancer, an ideal model characterized by complex crosstalk among Cancer metabolism, immune microenvironment, and immunotherapeutic resistance. The synergistic effect of CD73-specific drugs in combination with Immune Checkpoint blockade is observed in multiple pancreatic Cancer models. Cytometry by time-of-flight analysis shows that CD73 inhibition reduces tumor-infiltrating Tregs in pancreatic Cancer. Tumor cell-autonomous CD73 is found to facilitate Treg recruitment, in which CCL5 is identified as a significant downstream effector of CD73 using integrated proteomic and transcriptomic analyses. CD73 transcriptionally upregulates CCL5 through tumor cell-autocrine adenosine-Adora2a signaling-mediated activation of the p38-STAT1 axis, recruiting Tregs to pancreatic tumors and causing an immunosuppressive microenvironment. Together, this study highlights that CD73-adenosine metabolism transcriptionally controls pancreatic Cancer immunosuppression in a tumor-autonomous and -autocrine manner.

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