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Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3+ Regulatory T Cells (Tregs) in Human Cancers
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Abstract
Purpose: CTLA-4 was the first inhibitory immune checkpoint to be identified. Two mAbs, ipilimumab (IgG1) and tremelimumab (IgG2), which block the function of CTLA-4, have demonstrated durable clinical activity in a subset of patients with advanced solid malignancies by augmenting effector T-cell–mediated immune responses. Studies in mice suggest that anti-CTLA-4 mAbs may also selectively deplete intratumoral FOXP3+ regulatory T cells via an Fc-dependent mechanism. However, it is unclear whether the depletion of FOXP3+ cells occurs in patients with cancer treated with anti-CTLA-4 therapies. Experimental Design: Quantitative IHC was used to evaluate the densities of intratumoral CD4+, CD8+, and FOXP3+ cells in stage-matched melanoma (n = 19), prostate cancer (n = 17), and bladder cancer (n = 9) samples treated with ipilimumab and in paired melanoma tumors (n = 18) treated with tremelimumab. These findings were corroborated with multiparametric mass cytometry analysis of tumor-infiltrating cells from paired fresh melanoma tumors (n = 5) treated with ipilimumab. Results: Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment. Conclusions: Anti-CTLA-4 immunotherapy does not deplete FOXP3+ cells in human tumors, which suggests that their efficacy could be enhanced by modifying the Fc portions of the mAbs to enhance Fc-mediated depletion of intratumoral regulatory T cells. See related commentary by Quezada and Peggs, p. 1130
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“Anti-CTLA-4 therapy has been somewhat effective in melanoma and several other cancers, and blockade of the PD-1/PD-L1 axis is now first-line therapy for various tumor types, particularly melanoma and non-small cell lung carcinoma, with their combination being superior at the expense of enhanced adverse effects359,360.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [359]
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“Anti-CTLA-4 therapy has been somewhat effective in melanoma and several other cancers, and blockade of the PD-1/PD-L1 axis is now first-line therapy for various tumor types, particularly melanoma and non-small cell lung carcinoma, with their combination being superior at the expense of enhanced adverse effects359,360.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [359]
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Metadata
- Authors
- Sharma, A., Subudhi, S. K., Blando, J., Scutti, J., Vence, L., Wargo, J., Allison, J. P., Ribas, A., & Sharma, P.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of California, Los Angeles (US)
- Corresponding author
- Sharma, Padmanee
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2019-02-15
- Volume
- 25
- Issue
- 4
- Pages
- 1233-1238
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC6348141
- OpenAlex
- W4253193856
- Cited by
- 382
- References
- 33
- Citations by year
- 2026: 22 · 2025: 37 · 2024: 62 · 2023: 40 · 2022: 60 · 2021: 60 · 2020: 49 · 2019: 43
- FWCI
- 15.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | NIH | National Cancer Institute (NCI) (R01 CA1633793)
- Prostate Cancer Foundation (PCF) (2014 Stewart Rahr-PCF Young Investigator)
- 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 immunotherapy, Foxp3+ regulatory T cells, ipilimumab, tremelimumab, tumor-infiltrating lymphocytes, tumor microenvironment, melanoma, prostate cancer, bladder cancer, mass cytometry, immune checkpoint blockade
- MeSH terms
- Ipilimumab, Urinary Bladder Neoplasms, Female, Humans, Male, Melanoma, Prostatic Neoplasms, CD4-Positive T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Paraffin Embedding, CD8-Positive T-Lymphocytes, Cell Lineage, Forkhead Transcription Factors, Tumor Microenvironment, CTLA-4 Antigen, Antibodies, Monoclonal, Humanized
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