Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma
Alex B. Blair, … , Victoria Kim, Lei Zheng
Alex B. Blair, … , Victoria Kim, Lei Zheng
Published February 12, 2019
Citation Information: J Clin Invest. 2019;129(4):1742-1755. https://doi.org/10.1172/JCI124077.
View: Text | PDF
Research Article Immunology Oncology

IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma

  • Text
  • PDF
Abstract

Pancreatic ductal adenocarcinoma (PDAC) represents an immune quiescent tumor that is resistant to immune checkpoint inhibitors. Previously, our group has shown that a GM-CSF–secreting allogenic pancreatic tumor cell vaccine (GVAX) may prime the tumor microenvironment by inducing intratumoral T cell infiltration. Here, we show that untreated PDACs express minimal indoleamine-2,3-dioxygenase (IDO1); however, GVAX therapy induced IDO1 expression on tumor epithelia as well as vaccine-induced tertiary lymphoid aggregates. IDO1 expression plays a role in regulating the polarization of Th1, Th17, and possibly T regulatory cells in PDAC tumors. IDO1 inhibitor enhanced antitumor efficacy of GVAX in a murine model of PDACs. The combination of vaccine and IDO1 inhibitor enhanced intratumoral T cell infiltration and function, but adding anti–PD-L1 antibody to the combination did not offer further synergy and in fact may have had a negative interaction, decreasing the number of intratumoral effector T cells. Additionally, IDO1 inhibitor in the presence of vaccine therapy did not significantly modulate intratumoral myeloid-derived suppressor cells quantitatively, but diminished their suppressive effect on CD8+ proliferation. Our study supports the combination of IDO1 inhibitor and vaccine therapy; however, it does not support the combination of IDO1 inhibitor and anti–PD-1/PD-L1 antibody for T cell–inflamed tumors such as PDACs treated with vaccine therapy.

Authors

Alex B. Blair, Jennifer Kleponis, Dwayne L. Thomas II, Stephen T. Muth, Adrian G. Murphy, Victoria Kim, Lei Zheng

×

Figure 3

High IDO1 expression upregulation is associated with a shift to an antitumor immune cell environment.

Options: View larger image (or click on image) Download as PowerPoint
High IDO1 expression upregulation is associated with a shift to an antit...
(A) Total number of Tregs (CD4+CD25+Foxp3+) quantified by flow cytometry analysis in tumor-infiltrating lymphocytes of tumor-bearing mice of the Panc02 hemispleen model and indicated treatments. Data represent mean ± SEM from one representative experiment of 4–5 mice per treatment group, repeated twice. Comparisons of the (B) percentage of Th1 (CD45+CD3+CD8–Foxp3–RORgt–Tbet+), (C) Th2 (CD45+CD3+CD8–Foxp3–RORgt–GATA3+), and (D) Th0 (CD45+CD3+CD8–Foxp3–RORgt–Tbet–GATA3–) subsets of cells in IDO1hi and IDO1lo human PDACs treated with GVAX. Comparison of the percentage of (E) Th17+ cells (CD45+CD3+CD8–Foxp3–RORgt+) and (F) Tregs (CD45+CD3+CD8–Foxp3+) in lymphoid aggregates of IDO1hi and IDO1lo PDACs treated with GVAX. (G) Comparison of the cell density of CD8+ cells (CD45+CD3+CD8+) in IDO1hi and IDO1lo PDACs following GVAX treatment (n = 16). Expression was quantified using Image Analysis Software (Aperio). *P < 0.05, **P < 0.01; NS, not significant, by unpaired t test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts