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Cell-intrinsic PD-1 promotes proliferation in pancreatic cancer by targeting CYR61/CTGF via the hippo pathway.
- Source :
-
Cancer letters [Cancer Lett] 2019 Sep 28; Vol. 460, pp. 42-53. Date of Electronic Publication: 2019 Jun 22. - Publication Year :
- 2019
-
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.<br /> (Published by Elsevier B.V.)
- Subjects :
- Animals
Antineoplastic Agents, Immunological pharmacology
Apoptosis
Carcinoma, Pancreatic Ductal drug therapy
Carcinoma, Pancreatic Ductal immunology
Carcinoma, Pancreatic Ductal pathology
Cell Line, Tumor
Hippo Signaling Pathway
Humans
Male
Mice, Inbred NOD
Mice, SCID
Pancreatic Neoplasms drug therapy
Pancreatic Neoplasms immunology
Pancreatic Neoplasms pathology
Programmed Cell Death 1 Receptor antagonists & inhibitors
Programmed Cell Death 1 Receptor immunology
Signal Transduction
Tumor Burden
Xenograft Model Antitumor Assays
Carcinoma, Pancreatic Ductal metabolism
Cell Proliferation drug effects
Connective Tissue Growth Factor metabolism
Cysteine-Rich Protein 61 metabolism
Pancreatic Neoplasms metabolism
Programmed Cell Death 1 Receptor metabolism
Protein Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 460
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 31233838
- Full Text :
- https://doi.org/10.1016/j.canlet.2019.06.013