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Cell-intrinsic PD-1 promotes proliferation in pancreatic cancer by targeting CYR61/CTGF via the hippo pathway

Ning Pu1, Shanshan Gao2, Hanlin Yin3

  • 1Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.

Cancer Letters
|June 25, 2019
PubMed

Insights

Cell-intrinsic Programmed cell death protein-1 (PD-1) promotes pancreatic cancer growth by inhibiting MOB1 phosphorylation. Combining PD-1 therapy with Hippo pathway inhibitors shows synergistic tumor suppression, improving outcomes for pancreatic ductal adenocarcinoma patients.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is a challenging malignancy with limited treatment options.
  • Programmed cell death protein-1 (PD-1) monotherapy is effective in various cancers, but its role in PDAC is unclear.
  • Understanding intrinsic PD-1 mechanisms in pancreatic cancer is crucial for developing novel therapies.

Purpose of the Study:

  • To investigate the role and mechanism of cell-intrinsic PD-1 in pancreatic ductal adenocarcinoma.
  • To explore the correlation between intrinsic PD-1 expression and clinicopathological characteristics, including overall survival (OS).
  • To evaluate the potential of combining PD-1-targeted therapy with Hippo pathway inhibitors for PDAC treatment.

Main Methods:

  • Analysis of associations between clinicopathological characteristics and PDAC tissue microarrays.
  • Profiling and functional analyses of intrinsic PD-1 in PDAC cells.
  • In vitro and in vivo experiments to assess cancer proliferation and apoptosis.
  • Mechanistic studies involving PD-1 binding to MOB1 and Hippo signaling pathway components.
  • Combination treatment studies using Hippo inhibitors and anti-PD-1 agents.

Main Results:

  • Cell-intrinsic PD-1 expression significantly correlates with overall survival (OS) in PDAC patients.
  • Intrinsic PD-1 promotes tumor growth, enhances proliferation, and inhibits apoptosis independently of adaptive immunity.
  • PD-1 binds to MOB1, inhibiting its phosphorylation and activating the Hippo signaling pathway.
  • Combined treatment with Hippo inhibitors and anti-PD-1 demonstrated synergistic tumor suppression.
  • PD-1-mediated Hippo signaling activation affects CYR61 and CTGF, impacting survival outcomes.

Conclusions:

  • Cell-intrinsic PD-1 plays a significant role in PDAC progression and is linked to patient survival.
  • Targeting intrinsic PD-1, particularly in combination with Hippo pathway inhibitors, offers a promising strategy to enhance anti-tumor efficacy in PDAC.
  • A novel nomogram incorporating these findings shows improved predictive accuracy for OS compared to TNM staging alone.
Keywords:
Hippo signalingImmune checkpointNomogramPancreatic ductal adenocarcinomaProgrammed cell death protein-1

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