Cited by 967Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies

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Peggs, Karl S., Quezada, Sergio A., Chambers, Cynthia A., Korman, Alan J., Allison, James P.·2009·Journal of Experimental Medicine

Abstract

Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) is a critical negative regulator of immune responses. Uniquely among known inhibitory receptors, its genetic ablation results in a fulminating and fatal lymphoproliferative disorder. This central regulatory role led to the development of antibodies designed to block CTLA-4 activity in vivo, aiming to enhance immune responses against cancer. Despite their preclinical efficacy and promising clinical activity against late stage metastatic melanoma, the critical cellular targets for their activity remains unclear. In particular, debate has focused on whether the effector T cell (Teff) or regulatory T cell (T reg cell) compartment is the primary target of antibody-mediated blockade. We developed a mouse expressing human instead of mouse CTLA-4, allowing us to evaluate the independent contributions of CTLA-4 blockade of each T cell compartment during cancer immunotherapy in an in vivo model of mouse melanoma. The data show that although blockade on effector cells significantly improves tumor protection, unicompartmental blockade on regulatory cells completely fails to enhance antitumor responses. However, concomitant blockade of both compartments leads to a synergistic effect and maximal antitumor activity. We conclude that the combination of direct enhancement of Teff cell function and concomitant inhibition of T reg cell activity through blockade of CTLA-4 on both cell types is essential for mediating the full therapeutic effects of anti–CTLA-4 antibodies during cancer immunotherapy.

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Authors
Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J., & Allison, J. P.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • University of Massachusetts Chan Medical School (US)
  • Medarex, Inc., Milpitas, CA 95035 3
Corresponding author
Allison, James P.
Venue
Journal of Experimental Medicine
Published
2009-07-06
Volume
206
Issue
8
Pages
1717-1725
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
OpenAlex
W2013043293
Cited by
967
References
34
Citations by year
2026: 17 · 2025: 46 · 2024: 57 · 2023: 56 · 2022: 51 · 2021: 54 · 2020: 59 · 2019: 64 · 2018: 78 · 2017: 82 · 2016: 78 · 2015: 81 · 2014: 56 · 2013: 60 · 2012: 39
FWCI
20.80
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Cancer Research Institute
  • Bristol-Myers Squibb
  • Memorial Sloan-Kettering Cancer Center
  • University College London
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
CTLA-4, anti-CTLA-4 antibody, regulatory T cells, effector T cells, cancer immunotherapy, melanoma, immune checkpoint blockade, humanized mice, antitumor immunity, T cell tolerance
MeSH terms
Animals, Antibodies, Neoplasm, Humans, Immunosuppression Therapy, Immunotherapy, Melanoma, Experimental, Mice, Inbred C57BL, Mice, Transgenic, Recombinant Proteins, Antigens, CD, T-Lymphocyte Subsets, Mice, Knockout, Cell Line, Tumor, T-Lymphocytes, Regulatory, Mice, CTLA-4 Antigen, In Vitro Techniques

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