. 2020 Oct; 12:10411-10421.
doi: 10.2147/CMAR.S265828.

Regulatory T Cells in Cancer Immunotherapy: Basic Research Outcomes and Clinical Directions

Guoming Zeng 1 Libo Jin 2 Qinsi Ying 3 Haojie Chen 2 Murinda Charmaine Thembinkosi 2 Chunguang Yang 4 Jinlong Zhao 4 Hao Ji 2 Sue Lin 2 Renyi Peng 2 Maolan Zhang 1 Da Sun 2 
  • PMID: 33116895
  •     73 References
  •     4 citations


Cancer immunotherapy is a promising approach that has recently gained its importance in treating cancer. Despite various approaches of immunotherapies being used to target cancer cells, they are either not effective against all types of cancer or for all patients. Although efforts are being made to improve the cancer immunotherapy in all possible ways, one important hindrance that lowers the immune response to kill cancer cells is the infiltration of Regulatory T (Treg) cells into the tumor cells, favoring tumor progression, on one hand, and inhibiting the activation of T cells to respond to cancer cells, on the other hand. Therefore, new anti-cancer drugs and vaccines fail to show promising results against cancer. This is due to the infiltration of Treg cells into the tumor region and suppression of anti-cancer activity. Thus, regardless of various types of immunotherapies being practiced, understanding the mechanisms of how Treg cells favor tumor progression and inhibition of anti-cancer activity is worthwhile. Therefore, the review highlights the importance of Tregs cells and how depletion of Treg cells can pave the way to an effective immunotherapy by activating the immune responses against cancer.

Keywords: FoxP3; Treg cells; anti-cancer; cancer immunotherapy; targeting Treg cells.

Spatially selective depletion of tumor-associated regulatory T cells with near-infrared photoimmunotherapy.
Kazuhide Sato, Noriko Sato, +5 authors, Hisataka Kobayashi.
Sci Transl Med, 2016 Aug 19; 8(352). PMID: 27535621    Free PMC article.
CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation.
Hyoung-Pyo Kim, Warren J Leonard.
J Exp Med, 2007 Jun 27; 204(7). PMID: 17591856    Free PMC article.
Highly Cited.
Epigenetic mechanisms of regulation of Foxp3 expression.
Girdhari Lal, Jonathan S Bromberg.
Blood, 2009 Jul 31; 114(18). PMID: 19641188    Free PMC article.
Highly Cited. Review.
Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors.
Frederick Arce Vargas, Andrew J S Furness, +29 authors, Sergio A Quezada.
Immunity, 2017 Apr 16; 46(4). PMID: 28410988    Free PMC article.
Highly Cited.
FoxP3: a life beyond regulatory T cells.
Yang Liu, Pan Zheng.
Int J Clin Exp Pathol, 2008 Dec 17; 2(3). PMID: 19079616    Free PMC article.
Regulatory T cells in health and disease.
Ciriaco A Piccirillo.
Cytokine, 2008 Aug 30; 43(3). PMID: 18722786
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.
Highly Cited.
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.
Mechanisms of tumor evasion from the immune response.
Paulo C Rodríguez, Arnold H Zea, Augusto C Ochoa.
Cancer Chemother Biol Response Modif, 2004 Sep 02; 21. PMID: 15338755
Decreased Suppression and Increased Phosphorylated STAT3 in Regulatory T Cells are Associated with Benefit from Adjuvant PD-1 Blockade in Resected Metastatic Melanoma.
David M Woods, Rupal Ramakrishnan, +4 authors, Jeffrey S Weber.
Clin Cancer Res, 2018 Aug 23; 24(24). PMID: 30131384    Free PMC article.
Multiple antitumor mechanisms downstream of prophylactic regulatory T-cell depletion.
Michele W L Teng, Jeremy B Swann, +7 authors, Mark J Smyth.
Cancer Res, 2010 Mar 25; 70(7). PMID: 20332236
Targeting Treg cells in cancer immunotherapy.
Atsushi Tanaka, Shimon Sakaguchi.
Eur J Immunol, 2019 Jul 02; 49(8). PMID: 31257581
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.
Intratumoral immune cell infiltrates, FoxP3, and indoleamine 2,3-dioxygenase in patients with melanoma undergoing CTLA4 blockade.
Antoni Ribas, Begoña Comin-Anduix, +9 authors, Alistair J Cochran.
Clin Cancer Res, 2009 Jan 02; 15(1). PMID: 19118070
An essential role for Scurfin in CD4+CD25+ T regulatory cells.
Roli Khattri, Tom Cox, Sue-Ann Yasayko, Fred Ramsdell.
Nat Immunol, 2003 Mar 04; 4(4). PMID: 12612581
Highly Cited.
Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma.
Michinori Ogura, Takashi Ishida, +16 authors, Ryuzo Ueda.
J Clin Oncol, 2014 Mar 13; 32(11). PMID: 24616310
Highly Cited.
Regulatory T cells exert checks and balances on self tolerance and autoimmunity.
Kajsa Wing, Shimon Sakaguchi.
Nat Immunol, 2009 Dec 18; 11(1). PMID: 20016504
Highly Cited. Review.
Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells.
Julia K Polansky, Lisa Schreiber, +7 authors, Jochen Huehn.
J Mol Med (Berl), 2010 Jun 25; 88(10). PMID: 20574810    Free PMC article.
Highly Cited.
CD4+/CD25+ regulatory cells inhibit activation of tumor-primed CD4+ T cells with IFN-gamma-dependent antiangiogenic activity, as well as long-lasting tumor immunity elicited by peptide vaccination.
Noelia Casares, Laura Arribillaga, +6 authors, Juan J Lasarte.
J Immunol, 2003 Nov 25; 171(11). PMID: 14634104
Immunotherapy Approaches in Cancer Treatment.
Pavel Klener, Pavel Otáhal, Lucie Lateckova, Pavel Klener.
Curr Pharm Biotechnol, 2015 Jun 20; 16(9). PMID: 26087990
Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance.
Xuefang Cao, Sheng F Cai, +4 authors, Timothy J Ley.
Immunity, 2007 Oct 09; 27(4). PMID: 17919943
Highly Cited.
Roles of the immune system in cancer: from tumor initiation to metastatic progression.
Hugo Gonzalez, Catharina Hagerling, Zena Werb.
Genes Dev, 2018 Oct 03; 32(19-20). PMID: 30275043    Free PMC article.
Highly Cited. Review.
CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients.
Andrew J Rech, Rosemarie Mick, +13 authors, Robert H Vonderheide.
Sci Transl Med, 2012 May 18; 4(134). PMID: 22593175    Free PMC article.
Highly Cited.
Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse.
Gaynor J Bates, Stephen B Fox, +4 authors, Alison H Banham.
J Clin Oncol, 2006 Dec 01; 24(34). PMID: 17135638
Highly Cited.
FOXP3+ regulatory T cells and their functional regulation.
Zhiyuan Li, Dan Li, Andy Tsun, Bin Li.
Cell Mol Immunol, 2015 Feb 17; 12(5). PMID: 25683611    Free PMC article.
Depleting T regulatory cells by targeting intracellular Foxp3 with a TCR mimic antibody.
Tao Dao, Sung Soo Mun, +11 authors, David A Scheinberg.
Oncoimmunology, 2019 May 31; 8(7). PMID: 31143508    Free PMC article.
Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC).
Young Kwang Chae, Ayush Arya, +4 authors, Francis Giles.
J Immunother Cancer, 2018 May 18; 6(1). PMID: 29769148    Free PMC article.
Highly Cited. Review.
Treg therapy in transplantation: a general overview.
Marco Romano, Sim Lai Tung, Lesley Ann Smyth, Giovanna Lombardi.
Transpl Int, 2016 Dec 25; 30(8). PMID: 28012226
DNA methylation controls Foxp3 gene expression.
Julia K Polansky, Karsten Kretschmer, +7 authors, Jochen Huehn.
Eur J Immunol, 2008 May 22; 38(6). PMID: 18493985
Highly Cited.
T-regulatory cells: key players in tumor immune escape and angiogenesis.
Andrea Facciabene, Gregory T Motz, George Coukos.
Cancer Res, 2012 May 03; 72(9). PMID: 22549946    Free PMC article.
Highly Cited. Review.
Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients.
Joannes F M Jacobs, Cornelis J A Punt, +8 authors, Gosse J Adema.
Clin Cancer Res, 2010 Aug 26; 16(20). PMID: 20736326
Treg and CTLA-4: two intertwining pathways to immune tolerance.
Lucy S K Walker.
J Autoimmun, 2013 Jul 16; 45. PMID: 23849743    Free PMC article.
Highly Cited. Review.
Immunomodulatory TGF-β Signaling in Hepatocellular Carcinoma.
Jian Chen, Julian A Gingold, Xiaoping Su.
Trends Mol Med, 2019 Jul 30; 25(11). PMID: 31353124
Highly Cited. Review.
PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.
Michael A Curran, Welby Montalvo, Hideo Yagita, James P Allison.
Proc Natl Acad Sci U S A, 2010 Feb 18; 107(9). PMID: 20160101    Free PMC article.
Highly Cited.
T cell surveillance of oncogene-induced prostate cancer is impeded by T cell-derived TGF-β1 cytokine.
Moses K Donkor, Abira Sarkar, +5 authors, Ming O Li.
Immunity, 2011 Jul 16; 35(1). PMID: 21757379    Free PMC article.
Application of PD-1 Blockade in Cancer Immunotherapy.
Xiaomo Wu, Zhongkai Gu, +4 authors, Xiaolong Liu.
Comput Struct Biotechnol J, 2019 Jun 18; 17. PMID: 31205619    Free PMC article.
Highly Cited. Review.
α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFβ antibody to promote durable rejection and immunity in squamous cell carcinomas.
E Dodagatta-Marri, D S Meyer, +21 authors, R J Akhurst.
J Immunother Cancer, 2019 Mar 06; 7(1). PMID: 30832732    Free PMC article.
PD-1 Blockade Expands Intratumoral Memory T Cells.
Antoni Ribas, Daniel Sanghoon Shin, +14 authors, Begoña Comin-Anduix.
Cancer Immunol Res, 2016 Jan 21; 4(3). PMID: 26787823    Free PMC article.
Highly Cited.
Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.
Jason D Fontenot, Marc A Gavin, Alexander Y Rudensky.
Nat Immunol, 2003 Mar 04; 4(4). PMID: 12612578
Highly Cited.
CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion.
Brian Kavanagh, Shaun O'Brien, +6 authors, Lawrence Fong.
Blood, 2008 Jun 05; 112(4). PMID: 18523152    Free PMC article.
Clinical Impact of Regulatory T cells (Treg) in Cancer and HIV.
Theresa L Whiteside.
Cancer Microenviron, 2014 Nov 12; 8(3). PMID: 25385463    Free PMC article.
Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial.
Luana Calabrò, Aldo Morra, +8 authors, Michele Maio.
Lancet Oncol, 2013 Sep 17; 14(11). PMID: 24035405
Highly Cited.
Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer.
Yukiko Tone, Keiji Furuuchi, +3 authors, Masahide Tone.
Nat Immunol, 2007 Dec 25; 9(2). PMID: 18157133
Highly Cited.
Identification and validation of a tumor-infiltrating Treg transcriptional signature conserved across species and tumor types.
Angela M Magnuson, Evgeny Kiner, +8 authors, Christophe Benoist.
Proc Natl Acad Sci U S A, 2018 Oct 24; 115(45). PMID: 30348759    Free PMC article.
Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study.
Luana Calabrò, Aldo Morra, +10 authors, Michele Maio.
Lancet Respir Med, 2015 Mar 31; 3(4). PMID: 25819643
Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients.
Koji Kurose, Yoshihiro Ohue, +13 authors, Eiichi Nakayama.
Clin Cancer Res, 2015 Oct 03; 21(19). PMID: 26429981
Highly Cited.
Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.
M E Brunkow, E W Jeffery, +7 authors, F Ramsdell.
Nat Genet, 2001 Jan 04; 27(1). PMID: 11138001
Highly Cited.
High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients.
Daniel M Frey, Raoul A Droeser, +7 authors, Luigi Tornillo.
Int J Cancer, 2009 Oct 27; 126(11). PMID: 19856313
Highly Cited.
Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells.
Andrea Facciabene, Xiaohui Peng, +8 authors, George Coukos.
Nature, 2011 Jul 15; 475(7355). PMID: 21753853
Highly Cited.
Breakthrough of the year 2013. Cancer immunotherapy.
Jennifer Couzin-Frankel.
Science, 2013 Dec 21; 342(6165). PMID: 24357284
Highly Cited.
T Regulatory Cells and Priming the Suppressive Tumor Microenvironment.
Christina M Paluskievicz, Xuefang Cao, +3 authors, Jonathan S Bromberg.
Front Immunol, 2019 Nov 05; 10. PMID: 31681327    Free PMC article.
Transient ablation of regulatory T cells improves antitumor immunity in colitis-associated colon cancer.
Eva Pastille, Katrin Bardini, +14 authors, Astrid M Westendorf.
Cancer Res, 2014 Jun 08; 74(16). PMID: 24906621
Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines.
Michael A Morse, Amy C Hobeika, +4 authors, Timothy M Clay.
Blood, 2008 Jun 04; 112(3). PMID: 18519811    Free PMC article.
Highly Cited.
Transforming of the Tumor Microenvironment: Implications for TGF-β Inhibition in the Context of Immune-Checkpoint Therapy.
Stefanie Löffek.
J Oncol, 2019 Jan 12; 2018. PMID: 30631358    Free PMC article.
Transforming Growth Factor-β Signaling in Immunity and Cancer.
Eduard Batlle, Joan Massagué.
Immunity, 2019 Apr 18; 50(4). PMID: 30995507    Free PMC article.
Highly Cited. Review.
Administration of a CD25-directed immunotoxin, LMB-2, to patients with metastatic melanoma induces a selective partial reduction in regulatory T cells in vivo.
Daniel J Powell, Aloisio Felipe-Silva, +8 authors, Ira Pastan.
J Immunol, 2007 Sep 20; 179(7). PMID: 17878392    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.
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.
RETRACTED: Long non-coding RNA NEAT1 plays an important role in sepsis-induced acute kidney injury by targeting miR-204 and modulating the NF-κB pathway.
Yi Chen, Jialing Qiu, +6 authors, Dongxin Jiang.
Int Immunopharmacol, 2018 Apr 19; 59. PMID: 29669307
Highly Cited. Review.
Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection.
Shomyseh Sanjabi, Soyoung A Oh, Ming O Li.
Cold Spring Harb Perspect Biol, 2017 Jan 22; 9(6). PMID: 28108486    Free PMC article.
Highly Cited. Review.
The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature.
Ronald J deLeeuw, Sara E Kost, Juzer A Kakal, Brad H Nelson.
Clin Cancer Res, 2012 Apr 19; 18(11). PMID: 22510350
Highly Cited. Systematic Review.
Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.
S Sakaguchi, N Sakaguchi, +2 authors, M Toda.
J Immunol, 1995 Aug 01; 155(3). PMID: 7636184
Highly Cited.
PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer.
Takahiro Kamada, Yosuke Togashi, +13 authors, Hiroyoshi Nishikawa.
Proc Natl Acad Sci U S A, 2019 Apr 28; 116(20). PMID: 31028147    Free PMC article.
Highly Cited.
Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans.
Daisuke Sugiyama, Hiroyoshi Nishikawa, +10 authors, Shimon Sakaguchi.
Proc Natl Acad Sci U S A, 2013 Oct 16; 110(44). PMID: 24127572    Free PMC article.
Highly Cited.
Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells.
Kazushige Yoshida, Masanori Okamoto, +13 authors, Naoto Saito.
BMC Cancer, 2020 Jan 10; 20(1). PMID: 31914969    Free PMC article.
Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens.
Denise Golgher, Emma Jones, +2 authors, Awen Gallimore.
Eur J Immunol, 2003 Jan 31; 32(11). PMID: 12555672
Current status of interleukin-10 and regulatory T-cells in cancer.
Kristen L Dennis, Nichole R Blatner, Fotini Gounari, Khashayarsha Khazaie.
Curr Opin Oncol, 2013 Oct 01; 25(6). PMID: 24076584    Free PMC article.
Highly Cited. Review.
Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies.
Spencer C Wei, Nana-Ama A S Anang, +8 authors, James P Allison.
Proc Natl Acad Sci U S A, 2019 Oct 23; 116(45). PMID: 31636208    Free PMC article.
PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations.
Weiping Zou, Jedd D Wolchok, Lieping Chen.
Sci Transl Med, 2016 Mar 05; 8(328). PMID: 26936508    Free PMC article.
Highly Cited. Review.
CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients.
Chrysoula I Liakou, Ashish Kamat, +5 authors, Padmanee Sharma.
Proc Natl Acad Sci U S A, 2008 Sep 27; 105(39). PMID: 18818309    Free PMC article.
Highly Cited.
Single dose denileukin diftitox does not enhance vaccine-induced T cell responses or effectively deplete Tregs in advanced melanoma: immune monitoring and clinical results of a randomized phase II trial.
Jason J Luke, Yuanyuan Zha, Karen Matijevich, Thomas F Gajewski.
J Immunother Cancer, 2016 Jun 23; 4. PMID: 27330808    Free PMC article.
Cancer immunotherapy: harnessing the immune system to battle cancer.
Yiping Yang.
J Clin Invest, 2015 Sep 02; 125(9). PMID: 26325031    Free PMC article.
Highly Cited. Review.
Granzymes in cancer and immunity.
S P Cullen, M Brunet, S J Martin.
Cell Death Differ, 2010 Jan 16; 17(4). PMID: 20075940
Highly Cited. Review.
The Potentiation of Anti-Tumor Immunity by Tumor Abolition with Alpha Particles, Protons, or Carbon Ion Radiation and Its Enforcement by Combination with Immunoadjuvants or Inhibitors of Immune Suppressor Cells and Checkpoint Molecules.
Yona Keisari, Itzhak Kelson.
Cells, 2021 Jan 29; 10(2). PMID: 33503958    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.
Canonical Secretomes, Innate Immune Caspase-1-, 4/11-Gasdermin D Non-Canonical Secretomes and Exosomes May Contribute to Maintain Treg-Ness for Treg Immunosuppression, Tissue Repair and Modulate Anti-Tumor Immunity via ROS Pathways.
Dong Ni, TingTing Tang, +14 authors, Xiaofeng Yang.
Front Immunol, 2021 Jun 05; 12. PMID: 34084175    Free PMC article.
Immunopeptidomics-Guided Warehouse Design for Peptide-Based Immunotherapy in Chronic Lymphocytic Leukemia.
Annika Nelde, Yacine Maringer, +11 authors, Juliane S Walz.
Front Immunol, 2021 Jul 27; 12. PMID: 34305947    Free PMC article.