Cited by 1,008T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersImmunotherapy and Immune Responses

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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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Sutmuller, Roger P.M., van Duivenvoorde, Leonie M., van Elsas, Andrea, Schumacher, Ton N.M., Wildenberg, Manon E., Allison, James P., Toes, Rene E.M., Offringa, Rienk, Melief, Cornelis J.M.·2001·The Journal of Experimental Medicine

DOI 10.1084/jem.194.6.823PMC PMC2195955

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Abstract

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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Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells
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“H-2K b tetramers were produced as described previously (20, 21) and stored frozen in Tris-buffered saline/16% glycerol/0.”
Method
CD4+CD25+ Immunoregulatory T Cells Suppress Polyclonal T Cell Activation In Vitro by Inhibiting Interleukin 2 Production
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MethodSelf-citation
Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4
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CTLA-4 can function as a negative regulator of T cell activation
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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)
ORCID: Schumacher, Ton N.M.
Wildenberg, Manon E.
Allison, James P.
Offringa, Rienk
Melief, Cornelis J.M.
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
DOI: 10.1084/jem.194.6.823
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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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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