Journal Article
. 2018 Feb; 28(4):416-432.
doi: 10.1038/s41422-018-0011-0.

A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy

Xuexiang Du 1 Fei Tang 1 Mingyue Liu 1 Juanjuan Su 1 Yan Zhang 1 Wei Wu 1 Martin Devenport 2 Christopher A Lazarski 1 Peng Zhang 1 Xu Wang 1 Peiying Ye 1 Changyu Wang 3 Eugene Hwang 1 Tinghui Zhu 4 Ting Xu 4 Pan Zheng 5 Yang Liu 1 
  • PMID: 29472691
  •     50 References
  •     80 citations


It is assumed that anti-CTLA-4 antibodies cause tumor rejection by blocking negative signaling from B7-CTLA-4 interactions. Surprisingly, at concentrations considerably higher than plasma levels achieved by clinically effective dosing, the anti-CTLA-4 antibody Ipilimumab blocks neither B7 trans-endocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Consequently, Ipilimumab does not increase B7 on dendritic cells (DCs) from either CTLA4 gene humanized (Ctla4 h/h ) or human CD34+ stem cell-reconstituted NSG™ mice. In Ctla4 h/m mice expressing both human and mouse CTLA4 genes, anti-CTLA-4 antibodies that bind to human but not mouse CTLA-4 efficiently induce Treg depletion and Fc receptor-dependent tumor rejection. The blocking antibody L3D10 is comparable to the non-blocking Ipilimumab in causing tumor rejection. Remarkably, L3D10 progenies that lose blocking activity during humanization remain fully competent in inducing Treg depletion and tumor rejection. Anti-B7 antibodies that effectively block CD4 T cell activation and de novo CD8 T cell priming in lymphoid organs do not negatively affect the immunotherapeutic effect of Ipilimumab. Thus, clinically effective anti-CTLA-4 mAb causes tumor rejection by mechanisms that are independent of checkpoint blockade but dependent on the host Fc receptor. Our data call for a reappraisal of the CTLA-4 checkpoint blockade hypothesis and provide new insights for the next generation of safe and effective anti-CTLA-4 mAbs.

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Transl Lung Cancer Res, 2021 Apr 24; 10(3). PMID: 33889507    Free PMC article.
Development of bispecific antibodies in China: overview and prospects.
Jing Zhang, Jizu Yi, Pengfei Zhou.
Antib Ther, 2021 May 01; 3(2). PMID: 33928227    Free PMC article.
Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies.
Laura Gámez-Díaz, Markus G Seidel.
Front Pediatr, 2021 May 18; 9. PMID: 33996698    Free PMC article.
Nanotechnology synergized immunoengineering for cancer.
Deepak S Chauhan, Anupam Dhasmana, +6 authors, Murali M Yallapu.
Eur J Pharm Biopharm, 2021 Mar 29; 163. PMID: 33774162    Free PMC article.
Combining vaccines and immune checkpoint inhibitors to prime, expand, and facilitate effective tumor immunotherapy.
Julie M Collins, Jason M Redman, James L Gulley.
Expert Rev Vaccines, 2018 Jul 31; 17(8). PMID: 30058393    Free PMC article.
The Next-Generation of Combination Cancer Immunotherapy: Epigenetic Immunomodulators Transmogrify Immune Training to Enhance Immunotherapy.
Reza Bayat Mokhtari, Manpreet Sambi, +7 authors, Myron R Szewczuk.
Cancers (Basel), 2021 Jul 25; 13(14). PMID: 34298809    Free PMC article.
Transfer learning between preclinical models and human tumors identifies a conserved NK cell activation signature in anti-CTLA-4 responsive tumors.
Emily F Davis-Marcisak, Allison A Fitzgerald, +5 authors, Elana J Fertig.
Genome Med, 2021 Aug 12; 13(1). PMID: 34376232    Free PMC article.
Motility Dynamics of T Cells in Tumor-Draining Lymph Nodes: A Rational Indicator of Antitumor Response and Immune Checkpoint Blockade.
Yasuhiro Kanda, Taku Okazaki, Tomoya Katakai.
Cancers (Basel), 2021 Sep 29; 13(18). PMID: 34572844    Free PMC article.
Immunotherapy for Hepatocellular Carcinoma: Current Status and Future Prospects.
Zhuoyan Liu, Xuan Liu, +5 authors, Xiaotao Jiang.
Front Immunol, 2021 Oct 23; 12. PMID: 34675942    Free PMC article.
Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Progresses and Challenges.
Hao-Tian Liu, Meng-Jie Jiang, +5 authors, Jian-Hong Zhong.
Front Oncol, 2021 Nov 09; 11. PMID: 34745958    Free PMC article.
Emerging immunological strategies: recent advances and future directions.
Hongyun Zhao, Fan Luo, +2 authors, Rui-Hua Xu.
Front Med, 2021 Dec 08; 15(6). PMID: 34874513
Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors.
Nicola J Mason, Nicholas Chester, +6 authors, Don L Siegel.
MAbs, 2021 Dec 04; 13(1). PMID: 34856888    Free PMC article.
Combination therapy for mCRPC with immune checkpoint inhibitors, ADT and vaccine: A mathematical model.
Nourridine Siewe, Avner Friedman.
PLoS One, 2022 Jan 12; 17(1). PMID: 35015785    Free PMC article.
Fc-independent functions of anti-CTLA-4 antibodies contribute to anti-tumor efficacy.
Yosuke Sato, Cierra N Casson, +14 authors, Michael H Shaw.
Cancer Immunol Immunother, 2022 Mar 04;. PMID: 35237846
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, Saman Maleki Vareki.
Cancers (Basel), 2022 Mar 26; 14(6). PMID: 35326731    Free PMC article.
Enabling the next steps in cancer immunotherapy: from antibody-based bispecifics to multispecifics, with an evolving role for bioconjugation chemistry.
Fabien Thoreau, Vijay Chudasama.
RSC Chem Biol, 2022 Apr 02; 3(2). PMID: 35360884    Free PMC article.
Anti-CTLA-4 and anti-PD-1 immunotherapies repress tumor progression in preclinical breast and colon model with independent regulatory T cells response.
Tristan Rupp, Laurie Genest, +4 authors, Vincent Castagné.
Transl Oncol, 2022 Mar 28; 20. PMID: 35339889    Free PMC article.
Reprogramming the tumor microenvironment by genome editing for precision cancer therapy.
Ke Liu, Jia-Jia Cui, +5 authors, Ji-Ye Yin.
Mol Cancer, 2022 Apr 13; 21(1). PMID: 35410257    Free PMC article.
Dual Effect of Immune Cells within Tumour Microenvironment: Pro- and Anti-Tumour Effects and Their Triggers.
Alicia Cristina Peña-Romero, Esteban Orenes-Piñero.
Cancers (Basel), 2022 Apr 13; 14(7). PMID: 35406451    Free PMC article.
Identify the Prognostic and Immune Profile of VSIR in the Tumor Microenvironment: A Pan-Cancer Analysis.
Yuanyuan Liu, Jingwei Zhang, +12 authors, Quan Cheng.
Front Cell Dev Biol, 2022 May 03; 10. PMID: 35493077    Free PMC article.
The immune checkpoint B7x expands tumor-infiltrating Tregs and promotes resistance to anti-CTLA-4 therapy.
Peter John, Marc C Pulanco, +4 authors, Xingxing Zang.
Nat Commun, 2022 May 07; 13(1). PMID: 35523809    Free PMC article.
Association of CTLA-4 and IL-4 polymorphisms in viral induced liver cancer.
Maria Shabbir, Yasmin Badshah, +10 authors, Suhail Razak.
BMC Cancer, 2022 May 08; 22(1). PMID: 35525950    Free PMC article.
The Leading Role of the Immune Microenvironment in Multiple Myeloma: A New Target with a Great Prognostic and Clinical Value.
Vanessa Desantis, Francesco Domenico Savino, +5 authors, Monica Montagnani.
J Clin Med, 2022 May 15; 11(9). PMID: 35566637    Free PMC article.