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
Suppressing T cell motility induced by anti–CTLA-4 monotherapy improves antitumor effects
Maria Grazia Ruocco, … , Michael L. Dustin, Sandra Demaria
Maria Grazia Ruocco, … , Michael L. Dustin, Sandra Demaria
Published September 4, 2012
Citation Information: J Clin Invest. 2012;122(10):3718-3730. https://doi.org/10.1172/JCI61931.
View: Text | PDF
Research Article Oncology Article has an altmetric score of 2

Suppressing T cell motility induced by anti–CTLA-4 monotherapy improves antitumor effects

  • Text
  • PDF
Abstract

A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as cytotoxic T lymphocyte–associated protein 4 (CTLA-4). However, the determinants of response to anti–CTLA-4 mAb treatment remain incompletely understood. In murine models, anti–CTLA-4 mAbs alone fail to induce effective immune responses to poorly immunogenic tumors but are successful when combined with additional interventions, including local ionizing radiation (IR) therapy. We employed an established model based on control of a mouse carcinoma cell line to study endogenous tumor-infiltrating CD8+ T lymphocytes (TILs) following treatment with the anti–CTLA-4 mAb 9H10. Alone, 9H10 monotherapy reversed the arrest of TILs with carcinoma cells in vivo. In contrast, the combination of 9H10 and IR restored MHC class I–dependent arrest. After implantation, the carcinoma cells had reduced expression of retinoic acid early inducible–1 (RAE-1), a ligand for natural killer cell group 2D (NKG2D) receptor. We found that RAE-1 expression was induced by IR in vivo and that anti-NKG2D mAb blocked the TIL arrest induced by IR/9H10 combination therapy. These results demonstrate that anti–CTLA-4 mAb therapy induces motility of TIL and that NKG2D ligation offsets this effect to enhance TILs arrest and antitumor activity.

Authors

Maria Grazia Ruocco, Karsten A. Pilones, Noriko Kawashima, Michael Cammer, Julie Huang, James S. Babb, Mengling Liu, Silvia C. Formenti, Michael L. Dustin, Sandra Demaria

×

Figure 4

Upregulation of ICAM-1 and RAE-1γ on 4T1 cells after in vivo irradiation.

Options: View larger image (or click on image) Download as PowerPoint
Upregulation of ICAM-1 and RAE-1γ on 4T1 cells after in vivo irradiation...
Cxcr6+/gfp mice were injected s.c. with CFP+ 4T1 cells on day 0 and mock treated (Control) (n = 9) or treated with local IR in 2 doses of 12 Gy on days 13 and 14 (n = 9). Tumors were analyzed on day 16. To obtain sufficient material, we pooled tumors from 3 mice in each treatment group to obtain 3 independent samples. Data are representative of 3 experiments. (A) 4T1 tumor cells were identified as CFP+CD45–. Histograms show the expression of H2-Kd, ICAM-1, and RAE-1γ on the gated CFP+CD45– mock-treated (thin lines) and irradiated (bold lines) cells. Cells stained with isotype control (dashed lines). Bar graphs show MFI after subtraction of background of 3 samples ± SD. In vivo irradiation significantly increased ICAM-1 but not H2-Kd and induced the expression of RAE-1γ on 4T1 cells. (B) Expression of H2-Kd, ICAM-1, RAE-1γ, and H60 was compared in CFP+ 4T1 tumor cells cultured in vitro (blue lines) and CFP+ 4T1 tumor cells isolated from tumors implanted in mice (red lines). Gray lines, isotype control. H60 and RAE-1 molecules were equally undetectable on 4T1 cells from in vivo growing tumors digested with liberase or dissociated with EDTA, as described in Methods. Data are representative of 3 experiments.

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

Sign up for email alerts

Posted by 1 X users
On 3 Facebook pages
164 readers on Mendeley
1 readers on CiteULike
See more details