Cited by 243Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

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The ICOS/ICOSL Pathway Is Required for Optimal Antitumor Responses Mediated by Anti–CTLA-4 Therapy

Fu, Tihui, He, Qiuming, Sharma, Padmanee·2011·Cancer Research

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Abstract

The anti-CTL-associated antigen 4 (anti-CTLA-4) antibody ipilimumab is the first agent to show improved survival in a randomized phase III trial that enrolled patients with metastatic melanoma. Studies are ongoing to identify mechanisms that elicit clinical benefit in the setting of anti-CTLA-4 therapy. We previously reported that treated patients had an increase in the frequency of T cells expressing the inducible costimulator (ICOS) molecule, a T-cell-specific molecule that belongs to the CD28/CTLA-4/B7 immunoglobulin superfamily. ICOS and its ligand (ICOSL) have been shown to play diverse roles in T-cell responses such as mediating autoimmunity as well as enhancing the development/activity of regulatory T cells. These seemingly opposing roles have made it difficult to determine whether the ICOS/ICOSL pathway is necessary for antitumor responses. To determine whether the ICOS/ICOSL pathway might play a causal role in the antitumor effects mediated by anti-CTLA-4, we conducted studies in ICOS-sufficient and ICOS-deficient mice bearing B16/BL6 melanoma. We show that ICOS(+) T cells comprised a population of Th1 cytokine producing and tumor antigen-specific effector cells. Furthermore, in the absence of ICOS, antitumor T-cell responses elicited by anti-CTLA-4 are significantly diminished, thereby impairing tumor rejection. Our findings establish that the ICOS/ICOSL pathway is necessary for the optimal therapeutic effect of anti-CTLA-4, thus implicating this pathway as a target for future combinatorial strategies to improve the efficacy of anti-CTLA-4 therapy.

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Crossref · 10.1158/0008-5472.can-11-1138

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“Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is the prototypical coinhibitory molecule that opposes CD28mediated costimulation (3-5).”
Background
CTLA-4 can function as a negative regulator of T cell activation
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ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28
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“ICOSCD8T cells produce IFN-γ upon recognition of tumor antigen and the absence of ICOS results in diminished tumor antigen-specific T cell responses Since CD8 T cells have been shown to play a dominant role in tumor rejection in the B16/BL6 melanoma model treated with anti-CTLA-4 (7-9, 36), we investigated the impact…”
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Authors: Fu, T., He, Q., & Sharma, P.
Affiliations: The University of Texas MD Anderson Cancer Center (US)
ORCID: Sharma, Padmanee
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2011-08-11
Volume: 71
Issue: 16
Pages: 5445-5454
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-11-1138
OpenAlex: W2141756397
Cited by: 243
References: 48
Citations by year: 2026: 4 · 2025: 9 · 2024: 15 · 2023: 25 · 2022: 19 · 2021: 23 · 2020: 19 · 2019: 14 · 2018: 20 · 2017: 16 · 2016: 14 · 2015: 17 · 2014: 13 · 2013: 21 · 2012: 11
FWCI: 7.48
Type: journal article
Language: en
Open access: closed
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
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 blockade, ipilimumab, metastatic melanoma, B16-BL6 melanoma, antitumor T-cell responses, tumor rejection, CTLA-4, regulatory T cells, autoimmunity
MeSH terms: Animals, Enzyme-Linked Immunosorbent Assay, Melanoma, Experimental, Mice, Inbred C57BL, Proteins, Antigens, CD, Lymphocytes, Tumor-Infiltrating, Mice, CTLA-4 Antigen, Inducible T-Cell Co-Stimulator Ligand

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The ICOS/ICOSL Pathway Is Required for Optimal Antitumor Responses Mediated by Anti–CTLA-4 Therapy

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