Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
VentX expression in tumor-associated macrophages promotes phagocytosis and immunity against pancreatic cancers
Yi Le, … , Thomas Clancy, Zhenglun Zhu
Yi Le, … , Thomas Clancy, Zhenglun Zhu
Published June 23, 2020
Citation Information: JCI Insight. 2020;5(14):e137088. https://doi.org/10.1172/jci.insight.137088.
View: Text | PDF
Research Article Immunology

VentX expression in tumor-associated macrophages promotes phagocytosis and immunity against pancreatic cancers

  • Text
  • PDF
Abstract

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy that has no effective treatment. The tumor microenvironment (TME) of PDA employs a multitude of immune derangement strategies to protect PDA from immune elimination. Tumor-associated macrophages (TAMs) have been implicated in the pathogenesis of immune suppression of the PDA TME; however, its underlying mechanisms remained largely unknown. Using primary patient samples, our studies showed that, in comparison with macrophages isolated from normal pancreatic tissues, the phagocytosis activity of the PDA TAMs was significantly reduced. We found that the expression of homeobox protein VentX, a master regulator of macrophage plasticity, was significantly decreased in the PDA TAMs. We demonstrated that VentX was required for phagocytosis and that restoration of VentX expression in PDA TAMs promoted phagocytosis through the regulation of the signaling cascades involved in the process. Using an ex vivo culture model of primary human PDA, we showed that VentX-modulated TAMs transformed the PDA TME from a protumor milieu to an antitumor microenvironment by rectifying differentiation, proliferation, and activation of PDA-infiltrating immune cells. Using NSG-PDX models of primary human PDAs, we showed that VentX-modulated TAMs exerted strong inhibition on PDA tumorigenesis in vivo. Taken together, our data revealed a central mechanism underlying immune evasion of PDA and a potential novel venue to improve PDA prognosis.

Authors

Yi Le, Hong Gao, William Richards, Lei Zhao, Ronald Bleday, Thomas Clancy, Zhenglun Zhu

×

Figure 1

Characterization of pancreatic ductal adenocarcinoma.

Options: View larger image (or click on image) Download as PowerPoint
Characterization of pancreatic ductal adenocarcinoma.
(A) Representative...
(A) Representative images of H&E and vimentin immunostaining of pancreatic ductal adenocarcinoma (PDA) and control adjacent normal pancreatic tissue. Scale bar: 200 μm. (B) FACS analysis of CD68+ macrophages in pancreatic cancers. CD68+ macrophages in adjacent normal pancreatic tissue and PDA were analyzed by a flow cytometer. Blue shading represents isotype control, and red shading represents CD68+ cells. (C) Accounting of CD68+ macrophages in pancreatic cancer and adjacent normal pancreatic tissues. n = 6. **P < 0.01, paired Student’s t test. (D) The percentage of surface expression of M2 markers (CD163 and CD206) and M1 surface markers (CD40 and CD80) on CD68+ macrophages of adjacent normal pancreatic tissues and PDA TAMs from the same patients. Data are shown as the mean ± SD of 4 independent experiments. *P < 0.05, **P < 0.01, 1-way ANOVA with multiple comparisons was performed.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts