. 2022 Mar; 14(6):.
doi: 10.3390/cancers14061580.

Addressing the Elephant in the Immunotherapy Room: Effector T-Cell Priming versus Depletion of Regulatory T-Cells by Anti-CTLA-4 Therapy

Megan M Y Hong 1 Saman Maleki Vareki 1 
  • PMID: 35326731
  •     154 References


Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) is an immune checkpoint molecule highly expressed on regulatory T-cells (Tregs) that can inhibit the activation of effector T-cells. Anti-CTLA-4 therapy can confer long-lasting clinical benefits in cancer patients as a single agent or in combination with other immunotherapy agents. However, patient response rates to anti-CTLA-4 are relatively low, and a high percentage of patients experience severe immune-related adverse events. Clinical use of anti-CTLA-4 has regained interest in recent years; however, the mechanism(s) of anti-CTLA-4 is not well understood. Although activating T-cells is regarded as the primary anti-tumor mechanism of anti-CTLA-4 therapies, mounting evidence in the literature suggests targeting intra-tumoral Tregs as the primary mechanism of action of these agents. Tregs in the tumor microenvironment can suppress the host anti-tumor immune responses through several cell contact-dependent and -independent mechanisms. Anti-CTLA-4 therapy can enhance the priming of T-cells by blockading CD80/86-CTLA-4 interactions or depleting Tregs through antibody-dependent cellular cytotoxicity and phagocytosis. This review will discuss proposed fundamental mechanisms of anti-CTLA-4 therapy, novel uses of anti-CTLA-4 in cancer treatment and approaches to improve the therapeutic efficacy of anti-CTLA-4.

Keywords: ADCC/P; CD28 costimulation; CTLA-4; FOXP3; Tregs; anti-CTLA-4; immunotherapy; ipilimumab.

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Isotype selection for antibody-based cancer therapy.
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Clin Exp Immunol, 2020 Nov 07; 203(3). PMID: 33155272    Free PMC article.
Tumor-specific Th17-polarized cells eradicate large established melanoma.
Pawel Muranski, Andrea Boni, +14 authors, Nicholas P Restifo.
Blood, 2008 Mar 21; 112(2). PMID: 18354038    Free PMC article.
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Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo.
Rituparna Das, Rakesh Verma, +8 authors, Kavita M Dhodapkar.
J Immunol, 2014 Dec 30; 194(3). PMID: 25539810    Free PMC article.
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Ryan D Michalek, Valerie A Gerriets, +6 authors, Jeffrey C Rathmell.
J Immunol, 2011 Feb 15; 186(6). PMID: 21317389    Free PMC article.
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Th17 cells inhibit CD8+ T cell migration by systematically downregulating CXCR3 expression via IL-17A/STAT3 in advanced-stage colorectal cancer patients.
Dan Wang, Weina Yu, +13 authors, Yi Zhang.
J Hematol Oncol, 2020 Jun 07; 13(1). PMID: 32503584    Free PMC article.
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Udupi A Ramagopal, Weifeng Liu, +10 authors, Steven C Almo.
Proc Natl Acad Sci U S A, 2017 May 10; 114(21). PMID: 28484017    Free PMC article.
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Cancer Res, 2011 Feb 10; 71(4). PMID: 21303976
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Metabolic modeling of single Th17 cells reveals regulators of autoimmunity.
Allon Wagner, Chao Wang, +23 authors, Nir Yosef.
Cell, 2021 Jul 04; 184(16). PMID: 34216539    Free PMC article.
Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients.
Emanuela Romano, Monika Kusio-Kobialka, +7 authors, Daniel E Speiser.
Proc Natl Acad Sci U S A, 2015 Apr 29; 112(19). PMID: 25918390    Free PMC article.
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Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial.
Thomas Yau, Yoon-Koo Kang, +18 authors, Chiun Hsu.
JAMA Oncol, 2020 Oct 02; 6(11). PMID: 33001135    Free PMC article.
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M F Krummel, J P Allison.
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Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis.
Bin Shang, Yao Liu, Shu-juan Jiang, Yi Liu.
Sci Rep, 2015 Oct 16; 5. PMID: 26462617    Free PMC article.
Highly Cited. Systematic Review.
Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer.
Matthew D Hellmann, Luis Paz-Ares, +23 authors, Suresh S Ramalingam.
N Engl J Med, 2019 Sep 29; 381(21). PMID: 31562796
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CTLA-4 ligation blocks CD28-dependent T cell activation.
T L Walunas, C Y Bakker, J A Bluestone.
J Exp Med, 1996 Jun 01; 183(6). PMID: 8676075    Free PMC article.
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Ctla-4 controls regulatory T cell peripheral homeostasis and is required for suppression of pancreatic islet autoimmunity.
Emily M Schmidt, Chun Jing Wang, +7 authors, Lucy S K Walker.
J Immunol, 2008 Dec 26; 182(1). PMID: 19109158
Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
Caroline Robert, Luc Thomas, +21 authors, Jedd D Wolchok.
N Engl J Med, 2011 Jun 07; 364(26). PMID: 21639810
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Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3+ Regulatory T Cells (Tregs) in Human Cancers.
Anu Sharma, Sumit K Subudhi, +6 authors, Padmanee Sharma.
Clin Cancer Res, 2018 Jul 29; 25(4). PMID: 30054281    Free PMC article.
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Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
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Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads.
Danielle M Lussier, Elise Alspach, +10 authors, Robert D Schreiber.
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Immunol Lett, 2014 May 23; 161(1). PMID: 24845157
Vectorized Treg-depleting αCTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject 'cold' tumors.
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J Immunother Cancer, 2022 Jan 22; 10(1). PMID: 35058324    Free PMC article.
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Ajay V Maker, Peter Attia, Steven A Rosenberg.
J Immunol, 2005 Nov 23; 175(11). PMID: 16301685    Free PMC article.
Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy.
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Highly Cited. Review.
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Proc Natl Acad Sci U S A, 2018 Dec 28; 116(2). PMID: 30587582    Free PMC article.
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Regulatory T Cells in Ovarian Cancer Are Characterized by a Highly Activated Phenotype Distinct from that in Melanoma.
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PLoS One, 2010 May 11; 5(5). PMID: 20454651    Free PMC article.
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Safety and efficacy of quavonlimab, a novel anti-CTLA-4 antibody (MK-1308), in combination with pembrolizumab in first-line advanced non-small-cell lung cancer.
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OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection.
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CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients.
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CTLA4 blockade increases Th17 cells in patients with metastatic melanoma.
Erika von Euw, Thinle Chodon, +4 authors, Antoni Ribas.
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The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation.
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J Immunother Cancer, 2019 Apr 13; 7(1). PMID: 30975201    Free PMC article.
Combination of CTLA-4 and PD-1 blockers for treatment of cancer.
Anand Rotte.
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Highly Cited. Review.
Modulation of tryptophan catabolism by regulatory T cells.
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Nat Immunol, 2003 Oct 28; 4(12). PMID: 14578884
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Tumor-infiltrating CD4+ Th17 cells produce IL-17 in tumor microenvironment and promote tumor progression in human gastric cancer.
Takeshi Iida, Makoto Iwahashi, +9 authors, Hiroki Yamaue.
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Triggering of OX40 (CD134) on CD4(+)CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR.
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A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma.
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Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma.
Christian U Blank, Elisa A Rozeman, +21 authors, Ton N Schumacher.
Nat Med, 2018 Oct 10; 24(11). PMID: 30297911
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Generation and differentiation of IL-17-producing CD4+ T cells in malignant pleural effusion.
Zhi-Jian Ye, Qiong Zhou, +5 authors, Huan-Zhong Shi.
J Immunol, 2010 Oct 19; 185(10). PMID: 20952674
Interleukin-17 enhances bFGF-, HGF- and VEGF-induced growth of vascular endothelial cells.
Hidenori Takahashi, Muneo Numasaki, Michael T Lotze, Hidetada Sasaki.
Immunol Lett, 2005 Apr 30; 98(2). PMID: 15860217
Suppression of tumour-specific CD4⁺ T cells by regulatory T cells is associated with progression of human colorectal cancer.
Gareth Betts, Emma Jones, +9 authors, Andrew Godkin.
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Nat Rev Immunol, 2017 Oct 11; 18(3). PMID: 28990585
Highly Cited. Review.
Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab.
Zeynep Eroglu, Dae Won Kim, +9 authors, Antoni Ribas.
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Tumor microenvironments direct the recruitment and expansion of human Th17 cells.
Xinming Su, Jian Ye, +3 authors, Guangyong Peng.
J Immunol, 2009 Dec 23; 184(3). PMID: 20026736
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Mitochondrial complex III is essential for suppressive function of regulatory T cells.
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Jun Mitsui, Hiroyoshi Nishikawa, +9 authors, Hiroshi Shiku.
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