Journal Article
. 2008 Jun; 112(4):1175-83.
doi: 10.1182/blood-2007-11-125435.

CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion

Brian Kavanagh 1 Shaun O'Brien  David Lee  Yafei Hou  Vivian Weinberg  Brian Rini  James P Allison  Eric J Small  Lawrence Fong  
  • PMID: 18523152
  •     53 References
  •     113 citations


Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) delivers inhibitory signals to activated T cells. CTLA4 is constitutively expressed on regulatory CD4(+) T cells (Tregs), but its role in these cells remains unclear. CTLA4 blockade has been shown to induce antitumor immunity. In this study, we examined the effects of anti-CTLA4 antibody on the endogenous CD4(+) T cells in cancer patients. We show that CTLA4 blockade induces an increase not only in the number of activated effector CD4(+) T cells, but also in the number of CD4(+) FoxP3(+) Tregs. Although the effects were dose-dependent, CD4(+) FoxP3(+) regulatory T cells could be expanded at lower antibody doses. In contrast, expansion of effector T cells was seen only at the highest dose level studied. Moreover, these expanded CD4(+) FoxP3(+) regulatory T cells are induced to proliferate with treatment and possess suppressor function. Our results demonstrate that treatment with anti-CTLA4 antibody does not deplete human CD4(+) FoxP3(+) Tregs in vivo, but rather may mediate its effects through the activation of effector T cells. Our results also suggest that CTLA4 may inhibit Treg proliferation similar to its role on effector T cells. This study is registered at, registry number NCT00064129.

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Nat Rev Clin Oncol, 2015 Nov 26; 13(3). PMID: 26598942
Highly Cited. Review.
Novel technologies and emerging biomarkers for personalized cancer immunotherapy.
Jianda Yuan, Priti S Hegde, +16 authors, Bernard A Fox.
J Immunother Cancer, 2016 Jan 21; 4. PMID: 26788324    Free PMC article.
Highly Cited. Review.
Immunotherapy for Gastric Cancer: A Focus on Immune Checkpoints.
Maria Alsina, Markus Moehler, +2 authors, Josep Tabernero.
Target Oncol, 2016 Feb 18; 11(4). PMID: 26880697
Phenotypic and functional testing of circulating regulatory T cells in advanced melanoma patients treated with neoadjuvant ipilimumab.
Janet Retseck, Robert VanderWeele, +3 authors, Ahmad A Tarhini.
J Immunother Cancer, 2016 Jun 23; 4. PMID: 27330811    Free PMC article.
The role of regulatory T cells in cancer immunology.
Theresa L Whiteside.
Immunotargets Ther, 2015 Jan 01; 4. PMID: 27471721    Free PMC article.
Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting.
Belal Chaudhary, Eyad Elkord.
Vaccines (Basel), 2016 Aug 12; 4(3). PMID: 27509527    Free PMC article.
Highly Cited. Review.
Is There Still Room for Cancer Vaccines at the Era of Checkpoint Inhibitors.
Soumaya Karaki, Marie Anson, +4 authors, Eric Tartour.
Vaccines (Basel), 2016 Nov 10; 4(4). PMID: 27827885    Free PMC article.
Combined VEGFR and CTLA-4 blockade increases the antigen-presenting function of intratumoral DCs and reduces the suppressive capacity of intratumoral MDSCs.
Stephanie Du Four, Sarah K Maenhout, +3 authors, Joeri L Aerts.
Am J Cancer Res, 2016 Dec 03; 6(11). PMID: 27904768    Free PMC article.
TCR Signaling and CD28/CTLA-4 Signaling Cooperatively Modulate T Regulatory Cell Homeostasis.
Michael P Holt, George A Punkosdy, Deborah D Glass, Ethan M Shevach.
J Immunol, 2017 Jan 06; 198(4). PMID: 28053234    Free PMC article.
Immunoregulatory functions of VISTA.
Elizabeth C Nowak, J Louise Lines, +7 authors, Randolph J Noelle.
Immunol Rev, 2017 Mar 05; 276(1). PMID: 28258694    Free PMC article.
Highly Cited. Review.
Progress and opportunities for enhancing the delivery and efficacy of checkpoint inhibitors for cancer immunotherapy.
David M Francis, Susan N Thomas.
Adv Drug Deliv Rev, 2017 Apr 30; 114. PMID: 28455187    Free PMC article.
Antibody-mediated neutralization of soluble MIC significantly enhances CTLA4 blockade therapy.
Jingyu Zhang, Dai Liu, +4 authors, Jennifer D Wu.
Sci Adv, 2017 Jun 01; 3(5). PMID: 28560327    Free PMC article.
Ibrutinib treatment improves T cell number and function in CLL patients.
Meixiao Long, Kyle Beckwith, +17 authors, John C Byrd.
J Clin Invest, 2017 Jul 18; 127(8). PMID: 28714866    Free PMC article.
Highly Cited.
Checkpoint Inhibitors for Non-Small Cell Lung Cancer Among Older Adults.
Rawad Elias, Joshua Morales, Carolyn Presley.
Curr Oncol Rep, 2017 Jul 30; 19(9). PMID: 28755314
Targets for immunotherapy of liver cancer.
Tim F Greten, Bruno Sangro.
J Hepatol, 2017 Sep 20;. PMID: 28923358    Free PMC article.
Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity.
Pearl Bakhru, Meng-Lei Zhu, +14 authors, Maureen A Su.
JCI Insight, 2017 Sep 22; 2(18). PMID: 28931755    Free PMC article.
Checkpoint Inhibitors: Applications for Autoimmunity.
Anna S Tocheva, Adam Mor.
Curr Allergy Asthma Rep, 2017 Sep 29; 17(10). PMID: 28956259    Free PMC article.
Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition.
Xia Liu, Wei Mo, +5 authors, Guangyong Peng.
Nat Commun, 2018 Jan 18; 9(1). PMID: 29339767    Free PMC article.
Phenotypic and Functional Properties of Tumor-Infiltrating Regulatory T Cells.
Gap Ryol Lee.
Mediators Inflamm, 2018 Feb 22; 2017. PMID: 29463952    Free PMC article.
Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy.
Rajani Ravi, Kimberly A Noonan, +13 authors, Atul Bedi.
Nat Commun, 2018 Feb 23; 9(1). PMID: 29467463    Free PMC article.
Highly Cited.
Immune Monitoring of Cancer Patients Prior to and During CTLA-4 or PD-1/PD-L1 Inhibitor Treatment.
Antje Tunger, Maximilian Kießler, +4 authors, Marc Schmitz.
Biomedicines, 2018 Mar 02; 6(1). PMID: 29494517    Free PMC article.
Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints.
Lee-Shing Chang, Romualdo Barroso-Sousa, +3 authors, Le Min.
Endocr Rev, 2018 Sep 06; 40(1). PMID: 30184160    Free PMC article.
Peripheral immune-based biomarkers in cancer immunotherapy: can we realize their predictive potential?
Andrew B Nixon, Kurt A Schalper, +3 authors, Catherine Fleener.
J Immunother Cancer, 2019 Nov 30; 7(1). PMID: 31775882    Free PMC article.
T-Regulatory Cells In Tumor Progression And Therapy.
Amit Verma, Rohit Mathur, +3 authors, Bilikere S Dwarakanath.
Cancer Manag Res, 2020 Jan 11; 11. PMID: 31920383    Free PMC article.
Anti-CTLA-4 Activates Intratumoral NK Cells and Combined with IL15/IL15Rα Complexes Enhances Tumor Control.
Emilio Sanseviero, Erin M O'Brien, +16 authors, Erica L Stone.
Cancer Immunol Res, 2019 Jun 27; 7(8). PMID: 31239316    Free PMC article.
Cytotoxic T lymphocyte-associated antigen-4 gene polymorphisms and biliary atresia susceptibility in Chinese children.
Jia Liu, Yifan Yang, +6 authors, Shan Zheng.
Int J Clin Exp Pathol, 2018 May 01; 11(5). PMID: 31938405    Free PMC article.
Therapeutic Monoclonal Antibodies Targeting Immune Checkpoints for the Treatment of Solid Tumors.
Nicholas Gravbrot, Kacy Gilbert-Gard, +4 authors, Srinath Sundararajan.
Antibodies (Basel), 2019 Oct 24; 8(4). PMID: 31640266    Free PMC article.
A novel immunogenic mouse model of melanoma for the preclinical assessment of combination targeted and immune-based therapy.
Emily J Lelliott, Carleen Cullinane, +14 authors, Karen E Sheppard.
Sci Rep, 2019 Feb 06; 9(1). PMID: 30718660    Free PMC article.
Resistance to Checkpoint Inhibition in Cancer Immunotherapy.
Luisa Barrueto, Francheska Caminero, +3 authors, Rahul R Deshmukh.
Transl Oncol, 2020 Mar 03; 13(3). PMID: 32114384    Free PMC article.
CTLA-4: a moving target in immunotherapy.
Behzad Rowshanravan, Neil Halliday, David M Sansom.
Blood, 2017 Nov 10; 131(1). PMID: 29118008    Free PMC article.
Highly Cited. Review.
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.
An adapted anti-CTLA4 therapeutic aimed at mitigating the toxicities of checkpoint inhibition.
Jarushka Naidoo, Arbor Dykema, Franco D'Alessio.
J Clin Invest, 2018 Dec 12; 129(1). PMID: 30530990    Free PMC article.
Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity.
Chien-Chun Steven Pai, Donald M Simons, +22 authors, Lawrence Fong.
J Clin Invest, 2018 Dec 12; 129(1). PMID: 30530991    Free PMC article.
Depleting tumor-associated Tregs via nanoparticle-mediated hyperthermia to enhance anti-CTLA-4 immunotherapy.
Hongwei Chen, Xin Luan, +7 authors, Duxin Sun.
Nanomedicine (Lond), 2019 Dec 24; 15(1). PMID: 31868112    Free PMC article.
Development of immune checkpoint therapy for cancer.
Jill M Fritz, Michael J Lenardo.
J Exp Med, 2019 May 10; 216(6). PMID: 31068379    Free PMC article.
Highly Cited. Review.
Dawn of Monitoring Regulatory T Cells in (Pre-)clinical Studies: Their Relevance Is Slowly Recognised.
A Charlotte M T de Wolf, Carla A Herberts, Marcel H N Hoefnagel.
Front Med (Lausanne), 2020 Apr 18; 7. PMID: 32300597    Free PMC article.
Systematic Review.
T cell costimulation, checkpoint inhibitors and anti-tumor therapy.
Dipankar Nandi, Sanmoy Pathak, +6 authors, Vijayamahantesh.
J Biosci, 2020 Apr 30; 45. PMID: 32345776
Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies.
Rodolfo Daniel Cervantes-Villagrana, Damaris Albores-García, Alberto Rafael Cervantes-Villagrana, Sara Judit García-Acevez.
Signal Transduct Target Ther, 2020 Jun 20; 5(1). PMID: 32555170    Free PMC article.
Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer.
David Y Oh, Serena S Kwek, +17 authors, Lawrence Fong.
Cell, 2020 Jun 05; 181(7). PMID: 32497499    Free PMC article.
Immunological Targets for Immunotherapy: Inhibitory T Cell Receptors.
Diwakar Davar, Hassane M Zarour.
Methods Mol Biol, 2019 Sep 11; 2055. PMID: 31502146    Free PMC article.
Scientifically based combination therapies with immuno-oncology checkpoint inhibitors.
Hui Yi Chew, Riccardo Dolcetti, Fiona Simpson.
Br J Clin Pharmacol, 2020 May 07; 86(9). PMID: 32372470    Free PMC article.
Autoimmune thyroid disease and type 1 diabetes mellitus: same pathogenesis; new perspective?
Liyan Li, Shudong Liu, Junxia Yu.
Ther Adv Endocrinol Metab, 2020 Sep 26; 11. PMID: 32973994    Free PMC article.
iRGD Peptide as a Tumor-Penetrating Enhancer for Tumor-Targeted Drug Delivery.
Sujin Kang, Sooyeun Lee, Soyeun Park.
Polymers (Basel), 2020 Aug 28; 12(9). PMID: 32847045    Free PMC article.
Regulatory T Cells in Cancer Immunotherapy: Basic Research Outcomes and Clinical Directions.
Guoming Zeng, Libo Jin, +9 authors, Da Sun.
Cancer Manag Res, 2020 Oct 30; 12. PMID: 33116895    Free PMC article.
Immune Checkpoints and CAR-T Cells: The Pioneers in Future Cancer Therapies?
Negar Hosseinkhani, Afshin Derakhshani, +9 authors, Behzad Baradaran.
Int J Mol Sci, 2020 Nov 11; 21(21). PMID: 33167514    Free PMC article.
Ipilimumab in prostate cancer.
Nishith Singh, Ravi A Madan, James L Gulley.
Expert Opin Biol Ther, 2012 Dec 26; 13(2). PMID: 23265575    Free PMC article.
Anti-CTLA-4 monoclonal antibody improves efficacy of the glyceraldehyde-3-phosphate dehydrogenase protein vaccine against Schistosoma japonicum in mice.
Chun-Lian Tang, Jin-Feng Yang, +4 authors, Hong-Hua Zhou.
Parasitol Res, 2019 Jun 07; 118(7). PMID: 31168702
Modulation of regulatory T cell function and stability by co-inhibitory receptors.
Liliana E Lucca, Margarita Dominguez-Villar.
Nat Rev Immunol, 2020 Apr 10; 20(11). PMID: 32269380
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.
Inhibition of STAT3 augments antitumor efficacy of anti-CTLA-4 treatment against prostate cancer.
Kristina Witt, Susan Evans-Axelsson, +3 authors, Rebecka Hellsten.
Cancer Immunol Immunother, 2021 Apr 01; 70(11). PMID: 33786638    Free PMC article.
Immunotherapy and predictive immunologic profile: the tip of the iceberg.
Tatiana Cunha Pereira, Paulo Rodrigues-Santos, +7 authors, Gabriela Sousa.
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How to turn up the heat on the cold immune microenvironment of metastatic prostate cancer.
Jacob Stultz, Lawrence Fong.
Prostate Cancer Prostatic Dis, 2021 Apr 07; 24(3). PMID: 33820953    Free PMC article.
CTLA-4 in Regulatory T Cells for Cancer Immunotherapy.
Navid Sobhani, Dana Rae Tardiel-Cyril, +3 authors, Yong Li.
Cancers (Basel), 2021 Apr 04; 13(6). PMID: 33809974    Free PMC article.
Inhibition of acid sphingomyelinase increases regulatory T cells in humans.
Teresa Wiese, Fabio Dennstädt, +16 authors, Niklas Beyersdorf.
Brain Commun, 2021 Apr 27; 3(2). PMID: 33898989    Free PMC article.
Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer.
Meenal Sinha, Li Zhang, +14 authors, Lawrence Fong.
J Immunother Cancer, 2021 May 15; 9(5). PMID: 33986125    Free PMC article.
Miscell: An efficient self-supervised learning approach for dissecting single-cell transcriptome.
Hongru Shen, Yang Li, +13 authors, Xiangchun Li.
iScience, 2021 Oct 30; 24(11). PMID: 34712916    Free PMC article.
Hallmarks of response, resistance, and toxicity to immune checkpoint blockade.
Golnaz Morad, Beth A Helmink, Padmanee Sharma, Jennifer A Wargo.
Cell, 2021 Oct 09; 184(21). PMID: 34624224    Free PMC article.
Research Progress and Prospects for Polymeric Nanovesicles in Anticancer Drug Delivery.
Dan Li, Xi Zhang, Xiao Chen, Wei Li.
Front Bioeng Biotechnol, 2022 Mar 01; 10. PMID: 35223804    Free PMC article.
A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance.
Alexander C Huang, Roberta Zappasodi.
Nat Immunol, 2022 Mar 05; 23(5). PMID: 35241833    Free PMC article.
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.
Dynamic peripheral blood immune cell markers for predicting the response of patients with metastatic cancer to immune checkpoint inhibitors.
Chen Wei, Mengyu Wang, +8 authors, Ning Li.
Cancer Immunol Immunother, 2022 Jun 07;. PMID: 35661905