Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • 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
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity
Scott R. Walsh, … , John C. Bell, Yonghong Wan
Scott R. Walsh, … , John C. Bell, Yonghong Wan
Published November 13, 2018
Citation Information: J Clin Invest. 2019;129(2):518-530. https://doi.org/10.1172/JCI121004.
View: Text | PDF
Research Article Autoimmunity Vaccines

Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity

  • Text
  • PDF
Abstract

Despite its success in treating melanoma and hematological malignancies, adoptive cell therapy (ACT) has had only limited effects in solid tumors. This is due in part to a lack of specific antigen targets, poor trafficking and infiltration, and immunosuppression in the tumor microenvironment. In this study, we combined ACT with oncolytic virus vaccines (OVVs) to drive expansion and tumor infiltration of transferred antigen-specific T cells and demonstrated that the combination is highly potent for the eradication of established solid tumors. Consistent with other successful immunotherapies, this approach elicited severe autoimmune consequences when the antigen targeted was a self-protein. However, modulation of IFN-α/-β signaling, either by functional blockade or rational selection of an OVV backbone, ameliorated autoimmune side effects without compromising antitumor efficacy. Our study uncovers a pathogenic role for IFN-α/-β in facilitating autoimmune toxicity during cancer immunotherapy and presents a safe and powerful combinatorial regimen with immediate translational applications.

Authors

Scott R. Walsh, Donald Bastin, Lan Chen, Andrew Nguyen, Christopher J. Storbeck, Charles Lefebvre, David Stojdl, Jonathan L. Bramson, John C. Bell, Yonghong Wan

×

Figure 7

IFN-α/-β–induced upregulation of MHC I enhances antigen-specific cytotoxicity, resulting in autoimmune diabetes.

Options: View larger image (or click on image) Download as PowerPoint
IFN-α/-β–induced upregulation of MHC I enhances antigen-specific cytotox...
(A) Immunohistochemical staining of pancreatic tissues from treated RIP-gp mice showed increased MHC I expression on islets after VSV-gp33 and VacVΔB18R-gp33 treatment but only low MHC I expression levels on islet cells after treatment with VacV-gp33–based combination therapy. (B) Pancreatic islets showed intense MHC I staining upon i.p. injection with pIC on day 5 after treatment with the VacV-based combination therapy. Scale bar: 20 μm. (C) Flow cytometric evaluation of B16-gp33 cells treated in vitro with IFN-β showed upregulation of MHC I expression. (D) Combination therapy–generated cytotoxicity of CD8+ T cells on B16-gp33 cells but not gp33-negative B16F10 cells after pretreatment with IFN-β (n = 10). *P < 0.05 and ****P < 0.0001 by 2-way ANOVA with Holm-Sidak correction for multiple comparisons. (E) Tumor tissues from treated mice showed similar MHC I expression profiles when probed immunohistochemically, regardless of the viral vector used. Scale bars: 50 μm.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts