Cited by 390Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

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Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3+ Regulatory T Cells (Tregs) in Human Cancers

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Sharma, Anu, Subudhi, Sumit K., Blando, Jorge, Scutti, Jorge, Vence, Luis, Wargo, Jennifer, Allison, James P., Ribas, Antoni, Sharma, Padmanee·2019·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-18-0762PMC PMC6348141

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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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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: Sharma, Anu
Subudhi, Sumit K.
Blando, Jorge
Vence, Luis
Wargo, Jennifer
Allison, James P.
Ribas, Antoni
Sharma, Padmanee
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2019-02-15
Volume: 25
Issue: 4
Pages: 1233-1238
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-18-0762
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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Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3+ Regulatory T Cells (Tregs) in Human Cancers

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