Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25+ regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses
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Therapeutic efficacy of a tumor cell–based vaccine against experimental B16 melanoma requires the disruption of either of two immunoregulatory mechanisms that control autoreactive T cell responses: the cytotoxic T lymphocyte–associated antigen (CTLA)-4 pathway or the CD25+ regulatory T (Treg) cells. Combination of CTLA-4 blockade and depletion of CD25+ Treg cells results in maximal tumor rejection. Efficacy of the antitumor therapy correlates with the extent of autoimmune skin depigmentation as well as with the frequency of tyrosinase-related protein 2180–188–specific CTLs detected in the periphery. Furthermore, tumor rejection is dependent on the CD8+ T cell subset. Our data demonstrate that the CTL response against melanoma antigens is an important component of the therapeutic antitumor response and that the reactivity of these CTLs can be augmented through interference with immunoregulatory mechanisms. The synergism in the effects of CTLA-4 blockade and depletion of CD25+ Treg cells indicates that CD25+ Treg cells and CTLA-4 signaling represent two alternative pathways for suppression of autoreactive T cell immunity. Simultaneous intervention with both regulatory mechanisms is therefore a promising concept for the induction of therapeutic antitumor immunity.
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CD8+ T cells and CD4+ effector T cells have demonstrated anti-cancer potential, while regulatory T cells (CD4+ CD25+ Tregs) contribute to the attenuated immune response exhibited in cancer.
“CD8+ T cells and CD4+ effector T cells have demonstrated anti-cancer potential, while regulatory T cells (CD4+ CD25+ Tregs) have been shown to be able to contribute to the attenuated immune response exhibited in cancer [65,66].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [66]
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Self-citation
- Authors
- Sutmuller, R. P. M., van Duivenvoorde, L. M., van Elsas, A., Schumacher, T. N. M., Wildenberg, M. E., Allison, J. P., Toes, R. E. M., Offringa, R., & Melief, C. J. M.
- Affiliations
- Leiden University Medical Center (NL)
- aDepartment of Immunohematology and Blood Transfusion, Tumor Immunology Lab, E3-Q, Leiden University Medical Center, 2300 RC Leiden, Netherlands
- The Netherlands Cancer Institute (NL)
- University of California, Berkeley (US)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2001-09-17
- Volume
- 194
- Issue
- 6
- Pages
- 823-832
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2195955
- OpenAlex
- W2148911309
- Cited by
- 1,008
- References
- 44
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 8 · 2023: 12 · 2022: 15 · 2021: 15 · 2020: 18 · 2019: 11 · 2018: 12 · 2017: 25 · 2016: 22 · 2015: 36 · 2014: 26 · 2013: 48 · 2012: 41
- FWCI
- 13.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- CTLA-4 blockade, CD25+ regulatory T cells, Treg depletion, antitumor immunity, B16 melanoma, CD8+ T cells, tyrosinase-related protein 2, immune regulation, tumor rejection
- MeSH terms
- Abatacept, Animals, Antibodies, Monoclonal, Antigens, Differentiation, Antigens, Neoplasm, Female, Immunotherapy, Lymphocyte Depletion, Melanoma, Experimental, Mice, Inbred C57BL, Mice, Nude, T-Lymphocytes, Cytotoxic, Tumor Cells, Cultured, Receptors, Interleukin-2, Biomarkers, CD4-Positive T-Lymphocytes, Antigens, CD, Immunoconjugates, Intramolecular Oxidoreductases, Mice, CTLA-4 Antigen
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