. 2018 Dec; 39(12):953-956.
doi: 10.1016/

How Does an Anti-CTLA-4 Antibody Promote Cancer Immunity?

Yang Liu 1 Pan Zheng 2 
  • PMID: 30497614
  •     18 References
  •     24 citations


Anti-CTLA-4 antibodies can induce lasting protection for some melanoma patients. However, their therapeutic potential is limited by significant immunotherapy-related adverse effects (irAE). Here, we argue that the therapeutic effect may be based on an agonist activity that is fundamentally distinct, and can be therapeutically differentiated, from the antagonist activity responsible for irAE.

Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody.
S Onizuka, I Tawara, +3 authors, E Nakayama.
Cancer Res, 1999 Jul 09; 59(13). PMID: 10397255
Highly Cited.
Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.
Giao Q Phan, James C Yang, +14 authors, Steven A Rosenberg.
Proc Natl Acad Sci U S A, 2003 Jun 27; 100(14). PMID: 12826605    Free PMC article.
Highly Cited.
Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.
Tyler J Curiel, George Coukos, +18 authors, Weiping Zou.
Nat Med, 2004 Aug 24; 10(9). PMID: 15322536
Highly Cited.
Checkpoint blockade in cancer immunotherapy.
Alan J Korman, Karl S Peggs, James P Allison.
Adv Immunol, 2006 May 30; 90. PMID: 16730267    Free PMC article.
Highly Cited. Review.
Transcriptional regulation by Foxp3 is associated with direct promoter occupancy and modulation of histone acetylation.
Chunxia Chen, Emily A Rowell, +2 authors, Andrew D Wells.
J Biol Chem, 2006 Oct 10; 281(48). PMID: 17028180
CTLA-4 control over Foxp3+ regulatory T cell function.
Kajsa Wing, Yasushi Onishi, +5 authors, Shimon Sakaguchi.
Science, 2008 Oct 11; 322(5899). PMID: 18845758
Highly Cited.
Improved survival with ipilimumab in patients with metastatic melanoma.
F Stephen Hodi, Steven J O'Day, +26 authors, Walter J Urba.
N Engl J Med, 2010 Jun 08; 363(8). PMID: 20525992    Free PMC article.
Highly Cited.
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.
Highly Cited.
Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies.
Yannick Bulliard, Rose Jolicoeur, +6 authors, Jennifer L Brogdon.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897982    Free PMC article.
Highly Cited.
Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells.
Mark J Selby, John J Engelhardt, +4 authors, Alan J Korman.
Cancer Immunol Res, 2014 Apr 30; 1(1). PMID: 24777248
Highly Cited.
Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.
Hye Sun Kuehn, Weiming Ouyang, +33 authors, Gulbu Uzel.
Science, 2014 Sep 13; 345(6204). PMID: 25213377    Free PMC article.
Highly Cited.
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
James Larkin, Vanna Chiarion-Sileni, +28 authors, Jedd D Wolchok.
N Engl J Med, 2015 Jun 02; 373(1). PMID: 26027431    Free PMC article.
Highly Cited.
Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice.
Xuexiang Du, Mingyue Liu, +8 authors, Pan Zheng.
Cell Res, 2018 Feb 22; 28(4). PMID: 29463898    Free PMC article.
Highly Cited.
A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy.
Xuexiang Du, Fei Tang, +14 authors, Yang Liu.
Cell Res, 2018 Feb 24; 28(4). PMID: 29472691    Free PMC article.
Highly Cited.
Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens.
Jeremy D Waight, Dhan Chand, +14 authors, Nicholas S Wilson.
Cancer Cell, 2018 Jun 13; 33(6). PMID: 29894690    Free PMC article.
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.
Highly Cited.
Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4.
P Waterhouse, J M Penninger, +6 authors, T W Mak.
Science, 1995 Nov 10; 270(5238). PMID: 7481803
Highly Cited.
CTLA-4 can function as a negative regulator of T cell activation.
T L Walunas, D J Lenschow, +5 authors, J A Bluestone.
Immunity, 1994 Aug 01; 1(5). PMID: 7882171
Highly Cited.
The application of nanotechnology in enhancing immunotherapy for cancer treatment: current effects and perspective.
Yongjiang Li, Ciceron Ayala-Orozco, Pradipta Ranjan Rauta, Sunil Krishnan.
Nanoscale, 2019 Sep 19; 11(37). PMID: 31531445    Free PMC article.
CTLA-4 Immunohistochemistry and Quantitative Image Analysis for Profiling of Human Cancers.
Charles Brown, Farzad Sekhavati, +4 authors, Keith E Steele.
J Histochem Cytochem, 2019 Oct 15; 67(12). PMID: 31609157    Free PMC article.
Nanoparticle Delivery of Immunostimulatory Agents for Cancer Immunotherapy.
Jia Zhuang, Maya Holay, +3 authors, Liangfang Zhang.
Theranostics, 2019 Nov 07; 9(25). PMID: 31695803    Free PMC article.
Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 Antibodies.
Peng Zhang, Xinxin Xiong, +8 authors, Pan Zheng.
Cancers (Basel), 2020 Jan 30; 12(2). PMID: 31991588    Free PMC article.
Tumor-infiltrating immune cells in hepatocellular carcinoma: Tregs is correlated with poor overall survival.
SiZhe Yu, Yu Wang, +9 authors, Hui Guo.
PLoS One, 2020 Apr 03; 15(4). PMID: 32240238    Free PMC article.
Metal-Organic Framework Nanoparticle-Based Biomineralization: A New Strategy toward Cancer Treatment.
Chengchao Chu, Min Su, +4 authors, Gang Liu.
Theranostics, 2019 Jun 28; 9(11). PMID: 31244946    Free PMC article.
Preserving the CTLA-4 Checkpoint for Safer and More Effective Cancer Immunotherapy.
Yang Liu, Pan Zheng.
Trends Pharmacol Sci, 2019 Dec 15; 41(1). PMID: 31836191    Free PMC article.
New Treatments in Renal Cancer: The AhR Ligands.
Boris Itkin, Alastair Breen, +3 authors, Andrea Irene Loaiza-Perez.
Int J Mol Sci, 2020 May 24; 21(10). PMID: 32443455    Free PMC article.
Prognostic value of FoxP3 and CTLA-4 expression in patients with oral squamous cell carcinoma.
Kazushige Koike, Hironari Dehari, +10 authors, Akihiro Miyazaki.
PLoS One, 2020 Aug 14; 15(8). PMID: 32785290    Free PMC article.
Isolation of Two Novel Human Anti-CTLA-4 mAbs with Intriguing Biological Properties on Tumor and NK Cells.
Margherita Passariello, Cinzia Vetrei, +7 authors, Claudia De Lorenzo.
Cancers (Basel), 2020 Aug 13; 12(8). PMID: 32781690    Free PMC article.
Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review.
Kevin Dzobo, Dimakatso Alice Senthebane, +3 authors, Collet Dandara.
Cells, 2020 Aug 23; 9(8). PMID: 32823711    Free PMC article.
Generation of highly activated, antigen-specific tumor-infiltrating CD8+ T cells induced by a novel T cell-targeted immunotherapy.
Ava Vila-Leahey, Alecia MacKay, +3 authors, Marianne M Stanford.
Oncoimmunology, 2020 Sep 15; 9(1). PMID: 32923145    Free PMC article.
Structure of CTLA-4 complexed with a pH-sensitive cancer immunotherapeutic antibody.
Han Gao, Haiyan Cai, +7 authors, Aiwu Zhou.
Cell Discov, 2020 Dec 11; 6(1). PMID: 33298884    Free PMC article.
Emerging dynamics pathways of response and resistance to PD-1 and CTLA-4 blockade: tackling uncertainty by confronting complexity.
Allan Relecom, Maysaloun Merhi, +4 authors, Said Dermime.
J Exp Clin Cancer Res, 2021 Feb 20; 40(1). PMID: 33602280    Free PMC article.
Rethinking peripheral T cell tolerance: checkpoints across a T cell's journey.
Mohamed A ElTanbouly, Randolph J Noelle.
Nat Rev Immunol, 2020 Oct 21; 21(4). PMID: 33077935
Adverse events induced by immune checkpoint inhibitors.
Ana Luisa Perdigoto, Harriet Kluger, Kevan C Herold.
Curr Opin Immunol, 2021 Mar 01; 69. PMID: 33640598    Free PMC article.
Magnetic Nanostructures as Emerging Therapeutic Tools to Boost Anti-Tumour Immunity.
Stefano Persano, Pradip Das, Teresa Pellegrino.
Cancers (Basel), 2021 Jun 03; 13(11). PMID: 34073106    Free PMC article.
Adjuvant-free peptide vaccine targeting Clec9a on dendritic cells can induce robust antitumor immune response through Syk/IL-21 axis.
Shanshan Gou, Shuai Wang, +10 authors, Yanfeng Gao.
Theranostics, 2021 Jun 24; 11(15). PMID: 34158852    Free PMC article.
Combination Immunotherapies to Overcome Intrinsic Resistance to Checkpoint Blockade in Microsatellite Stable Colorectal Cancer.
Chang Woo Kim, Hong Jae Chon, Chan Kim.
Cancers (Basel), 2021 Oct 14; 13(19). PMID: 34638390    Free PMC article.
Signal pathways of melanoma and targeted therapy.
Weinan Guo, Huina Wang, Chunying Li.
Signal Transduct Target Ther, 2021 Dec 21; 6(1). PMID: 34924562    Free PMC article.
Developing and characterizing a single-domain antibody (nanobody) against human cytotoxic T-lymphocyte-associated protein 4 (hCTLA-4).
Nazli Sotoudeh, Zahra Noormohammadi, +2 authors, Mahdi Behdani.
Iran J Basic Med Sci, 2022 Jan 28; 24(9). PMID: 35083014    Free PMC article.
Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events.
Remo Poto, Teresa Troiani, +4 authors, Gilda Varricchi.
Front Immunol, 2022 Apr 19; 13. PMID: 35432346    Free PMC article.
Dissecting the Role of Immune Checkpoint Regulation Patterns in Tumor Microenvironment and Prognosis of Gastric Cancer.
Zili Zhen, Zhemin Shen, Peilong Sun.
Front Genet, 2022 May 07; 13. PMID: 35518357    Free PMC article.
Engineering Induced Pluripotent Stem Cells for Cancer Immunotherapy.
Yang Zhou, Miao Li, +7 authors, Lili Yang.
Cancers (Basel), 2022 May 15; 14(9). PMID: 35565395    Free PMC article.