Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or VSports app下载. mil. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely V体育官网. .

. 2019 Feb 15;25(4):1233-1238.
doi: 10.1158/1078-0432.CCR-18-0762. Epub 2018 Jul 27.

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

Anu Sharma #  1 , Sumit K Subudhi #  1 , Jorge Blando  2 , Jorge Scutti  2 , Luis Vence  2 , Jennifer Wargo  3 , James P Allison  2 , Antoni Ribas  4 , Padmanee Sharma  5   2
Affiliations

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

Anu Sharma et al. Clin Cancer Res. .

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 VSports手机版. .

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 V体育安卓版. .

Results: Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment. V体育ios版.

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 VSports最新版本. .

PubMed Disclaimer

Conflict of interest statement

Conflict of interest

Drs. Sharma an Allison are founders of Jounce Therapeutics. Dr. Sharma also serves as a consultant for Bristol-Myers Squibb (BMS), Amgen, Constellation Pharmaceuticals, Jounce Therapeutics, Kite Pharma, Evelo, Neon Therapeutics, EMD Serono, Astellas Pharma, AstraZeneca, BioAtla, Pieris Pharmaceuticals, Oncolytics Biotech, Merck Sharp & Dohme. Dr VSports注册入口. Allison is an inventor and recipient of royalty from intellectual property licensed to BMS and Merck and is also a consultant for Jounce Therapeutics, Neon Therapeutics, Amgen and Kite Pharma. All other authors have no relevant conflicts of interest to disclose.

Figures

Figure 1:
Figure 1:. CTLA-4 blockade expands CD4+ and CD8+ cells
A) Stage-matched untreated (N=18) and ipilimumab (Ipi)-treated (N=16) metastatic melanoma tumor samples, and B) metastatic melanoma tumor samples (N=18) pre- and post-tremelimumab (Treme) treatment were analyzed by IHC for the presence of CD4+ and CD8+ cells. Each plot shows mean with standard deviation (SD), and each symbol represents an individual patient. Statistical significance is defined as P < 0.05.
Figure 2:
Figure 2:. Effect of CTLA-4 blockade on FOXP3+ cells in human melanoma
A) Stage-matched untreated (N=19) Ipi-treated (N=16) metastatic melanoma tumor samples, and B) metastatic melanoma tumor samples pre- and post-Treme treatment (N=11) were analyzed by IHC for the presence of FOXP3+ cells. Each plot shows mean with SD, and each symbol represents an individual patient. Statistical significance is defined as P < 0.05.
Figure 3:
Figure 3:. Effect of CTLA-4 blockade on FOXP3+ cells in bladder and prostate tumors
A) Stage-matched untreated and Ipi-treated bladder tumors (N=9), and B) prostate tumors (N=16) were analyzed by IHC for the presence of FOXP3+ cells. Each plot shows mean with SD, and each symbol represents an individual patient. Statistical significance is defined as P < 0.05.
Figure 4:
Figure 4:. Effect of CTLA-4 blockade on CD68+ cells
Stage-matched untreated and Ipi-treated (N=16) metastatic melanoma samples were analyzed by IHC for the presence of CD68+ cells. Each plot shows mean with SD, and each symbol represents an individual patient. Statistical significance is defined as P < 0.05.
See this image and copyright information in PMC

"V体育安卓版" Comment in

References

    1. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994;1(5):405–13. - PubMed
    1. Krummel MF, and Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. The Journal of experimental medicine. 1995;182(2):459–65. - PMC (VSports最新版本) - PubMed
    1. Leach DR, Krummel MF, and Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734–6. - PubMed
    1. Sharma P, and Allison JP. The future of immune checkpoint therapy. Science. 2015;348(6230):56–61. - VSports - PubMed
    1. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. The Journal of experimental medicine. 2013;210(9):1695–710. - PMC - PubMed

Publication types

MeSH terms