The ICOS/ICOSL Pathway Is Required for Optimal Antitumor Responses Mediated by Anti–CTLA-4 Therapy
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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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ICOS and TIM3 expressions on specific T cell subsets are related to antitumor immunity.
“ICOS and TIM3 expressions on specific T cells subsets are also related to antitumor immunity.52,53”
From The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti–Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC (2019) · cites this paper as [53]
mTORC1 activation is associated with ICOS expression, a T cell coregulatory receptor on tumor-infiltrating T cells associated with clinical response.
“mTORC1 activation has been associated with ICOS expression, a T cell coregulatory receptor seen on tumor-infiltrating T cells that has been associated with clinical response (67).”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [67]
Immune monitoring studies from that trial identified ICOS-positive CD4 T cells as a novel T-cell subset associated with anti-CTLA4 therapy.
“In addition, the immune monitoring studies performed on the trial highlighted the reverse translational approach and identified ICOS + CD4 T cells as a novel subset of T cells associated with anti-CTLA4 therapy (17,18,171,172).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [171]
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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
- Published
- 2011-08-11
- Volume
- 71
- Issue
- 16
- Pages
- 5445-5454
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- 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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