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

Ning Pu, Shanshan Gao, Hanlin Yin, Jian ang Li, Wenchuan Wu, Yuan Fang, Lei Zhang, Yefei Rong, Xuefeng Xu, Dansong Wang, Tiantao Kuang, Dayong Jin, Jun Yu, Wenhui Lou

Research output: Contribution to journalArticlepeer-review

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a refractory disease. Programmed cell death protein-1 (PD-1) monotherapy has shown strong performance in targeting several malignancies. However, the effect and mechanism of intrinsic PD-1 in pancreatic cancer cells is still unknown. In this study, associations between clinicopathological characteristics and stained tissue microarrays of PDAC specimens were analyzed along with profiling and functional analyses. The results showed that cell-intrinsic PD-1 was significantly correlated with overall survival (OS). Independently of adaptive immunity, intrinsic PD-1 promoted tumor growth in PDAC. Concomitantly, the overexpression of intrinsic PD-1 enhanced cancer proliferation and inhibited cell apoptosis in vitro and in vivo. Mechanistically, PD-1 binds to the downstream MOB1, thereby inhibiting its phosphorylation. Moreover, greater synergistic tumor suppression in vitro resulted from combining Hippo inhibitors with anti-PD-1 treatment compared with the suppression achieved by either single agent alone. Additionally, Hippo downstream targets, CYR61 (CCN1) and CTGF (CCN2), were directly affected by PD-1 mediated Hippo signaling activation in concert with survival outcomes. Finally, the formulated nomogram showed superior predictive accuracy for OS in comparison with the TNM stage alone. Therefore, PD-1 immunotherapy in combination with Hippo pathway inhibitors may optimize the anti-tumor efficacy in PDAC patients via targeting cell-intrinsic PD-1.

Original languageEnglish (US)
Pages (from-to)42-53
Number of pages12
JournalCancer Letters
Volume460
DOIs
StatePublished - Sep 28 2019

Keywords

  • Hippo signaling
  • Immune checkpoint
  • Nomogram
  • Pancreatic ductal adenocarcinoma
  • Programmed cell death protein-1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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