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Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies
Open accessAbstract
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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“However, depletion of Tregs alone does not enhance anti-tumor responses; rather, a combination of enhanced effector T cell function and the inhibition of Treg activity is necessary for maximal anti-tumor activity [119].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [119]
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“Blocking CTLA-4 with antibodies increases CD8+ lymphocytes and depletes Tregs.”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [119]
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Metadata
- 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
- Publisher
- Rockefeller University Press
- Published
- 2009-07-06
- Volume
- 206
- Issue
- 8
- Pages
- 1717-1725
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2722174
- 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
- bronze
- doi.org
- 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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