Journal Article
. 2014 Dec; 194(3):878-82.
doi: 10.4049/jimmunol.1402725.

Cutting edge: epigenetic regulation of Foxp3 defines a stable population of CD4+ regulatory T cells in tumors from mice and humans

Jeremy D Waight 1 Shinji Takai 2 Bo Marelli 1 Guozhong Qin 1 Kenneth W Hance 1 Dong Zhang 1 Robert Tighe 1 Yan Lan 1 Kin-Ming Lo 1 Helen Sabzevari 1 Robert Hofmeister 3 Nicholas S Wilson 4 
  • PMID: 25548231
  •     19 References
  •     31 citations


CD4(+) regulatory T cells (Tregs) are critical for maintaining self-tolerance and function to prevent autoimmune disease. High densities of intratumoral Tregs are generally associated with poor patient prognosis, a correlation attributed to their broad immune-suppressive features. Two major populations of Tregs have been defined, thymically derived natural Tregs (nTregs) and peripherally induced Tregs (iTregs). However, the relative contribution of nTregs versus iTregs to the intratumoral Treg compartment remains controversial. Demarcating the proportion of nTregs versus iTregs has important implications in the design of therapeutic strategies to overcome their antagonistic effects on antitumor immune responses. We used epigenetic, phenotypic, and functional parameters to evaluate the composition of nTregs versus iTregs isolated from mouse tumor models and primary human tumors. Our findings failed to find evidence for extensive intratumoral iTreg induction. Rather, we identified a population of Foxp3-stable nTregs in tumors from mice and humans.

A central role for induced regulatory T cells in tolerance induction in experimental colitis.
Dipica Haribhai, Wen Lin, +7 authors, Calvin B Williams.
J Immunol, 2009 Mar 07; 182(6). PMID: 19265124    Free PMC article.
Highly Cited.
Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation.
Hiromasa Morikawa, Naganari Ohkura, +11 authors, FANTOM Consortium.
Proc Natl Acad Sci U S A, 2014 Apr 08; 111(14). PMID: 24706905    Free PMC article.
Transforming growth factor-beta1 level correlates with angiogenesis, tumor progression, and prognosis in patients with nonsmall cell lung carcinoma.
Y Hasegawa, S Takanashi, +3 authors, K Okumura.
Cancer, 2001 Mar 17; 91(5). PMID: 11251948
Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells.
L Gorelik, R A Flavell.
Nat Med, 2001 Oct 09; 7(10). PMID: 11590434
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.
T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells.
Linda Fahlén, Simon Read, +4 authors, Fiona Powrie.
J Exp Med, 2005 Mar 09; 201(5). PMID: 15753207    Free PMC article.
Highly Cited.
Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation.
François Ghiringhelli, Pierre E Puig, +7 authors, Laurence Zitvogel.
J Exp Med, 2005 Sep 28; 202(7). PMID: 16186184    Free PMC article.
Highly Cited.
Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance.
Gang Zhou, Hyam I Levitsky.
J Immunol, 2007 Feb 06; 178(4). PMID: 17277120
A kinetic and dynamic analysis of Foxp3 induced in T cells by TGF-beta.
Ramesh K Selvaraj, Terrence L Geiger.
J Immunol, 2007 Jun 06; 178(12). PMID: 17548603
Antibody-mediated blockade of integrin alpha v beta 6 inhibits tumor progression in vivo by a transforming growth factor-beta-regulated mechanism.
Louise A Koopman Van Aarsen, Diane R Leone, +17 authors, Shelia M Violette.
Cancer Res, 2008 Jan 18; 68(2). PMID: 18199553
OX40 engagement depletes intratumoral Tregs via activating FcγRs, leading to antitumor efficacy.
Yannick Bulliard, Rose Jolicoeur, +3 authors, Jennifer L Brogdon.
Immunol Cell Biol, 2014 Apr 16; 92(6). PMID: 24732076
Highly Cited.
Tumor-derived TGF-beta mediates conversion of CD4+Foxp3+ regulatory T cells in a murine model of pancreas cancer.
Tricia A Moo-Young, Justin W Larson, +5 authors, David C Linehan.
J Immunother, 2009 Mar 25; 32(1). PMID: 19307989    Free PMC article.
Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate.
Ye Zheng, Steven Josefowicz, +3 authors, Alexander Y Rudensky.
Nature, 2010 Jan 15; 463(7282). PMID: 20072126    Free PMC article.
Highly Cited.
Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells.
Takahisa Miyao, Stefan Floess, +5 authors, Shohei Hori.
Immunity, 2012 Feb 14; 36(2). PMID: 22326580
Highly Cited.
T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development.
Naganari Ohkura, Masahide Hamaguchi, +12 authors, Shimon Sakaguchi.
Immunity, 2012 Nov 06; 37(5). PMID: 23123060
Highly Cited.
Aire-dependent thymic development of tumor-associated regulatory T cells.
Sven Malchow, Daniel S Leventhal, +9 authors, Peter A Savage.
Science, 2013 Mar 09; 339(6124). PMID: 23471412    Free PMC article.
Highly Cited.
Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma.
Stephen R Goding, Kyle A Wilson, +7 authors, Paul Andrew Antony.
J Immunol, 2013 Mar 29; 190(9). PMID: 23536636    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.
T cell metabolic fitness in antitumor immunity.
Peter J Siska, Jeffrey C Rathmell.
Trends Immunol, 2015 Mar 17; 36(4). PMID: 25773310    Free PMC article.
Highly Cited. Review.
Immunosuppressive Mechanisms of Malignant Gliomas: Parallels at Non-CNS Sites.
Powell Perng, Michael Lim.
Front Oncol, 2015 Jul 29; 5. PMID: 26217588    Free PMC article.
Regulatory and T Effector Cells Have Overlapping Low to High Ranges in TCR Affinities for Self during Demyelinating Disease.
Jennifer D Hood, Veronika I Zarnitsyna, Cheng Zhu, Brian D Evavold.
J Immunol, 2015 Sep 20; 195(9). PMID: 26385521    Free PMC article.
Analysis of the immune microenvironment in resected non-small cell lung cancer: the prognostic value of different T lymphocyte markers.
Marta Usó, Eloisa Jantus-Lewintre, +11 authors, Rafael Sirera.
Oncotarget, 2016 Jul 28; 7(33). PMID: 27463005    Free PMC article.
Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer.
Eleonora Timperi, Ilenia Pacella, +12 authors, Silvia Piconese.
Oncoimmunology, 2016 Sep 14; 5(7). PMID: 27622025    Free PMC article.
Histone Posttranslational Modifications of CD4⁺ T Cell in Autoimmune Diseases.
Zijun Wang, Heng Yin, Chak Sing Lau, Qianjin Lu.
Int J Mol Sci, 2016 Sep 27; 17(10). PMID: 27669210    Free PMC article.
Lactobacillus casei regulates differentiation of Th17/Treg cells to reduce intestinal inflammation in mice.
Kai Wang, Hao Dong, +8 authors, Guixue Hu.
Can J Vet Res, 2017 Apr 15; 81(2). PMID: 28408780    Free PMC article.
Interplay of Regulatory T Cell and Th17 Cells during Infectious Diseases in Humans and Animals.
Sharvan Sehrawat, Barry T Rouse.
Front Immunol, 2017 Apr 20; 8. PMID: 28421070    Free PMC article.
Chemo-Immunotherapy: Role of Indoleamine 2,3-Dioxygenase in Defining Immunogenic Versus Tolerogenic Cell Death in the Tumor Microenvironment.
Theodore S Johnson, Tracy Mcgaha, David H Munn.
Adv Exp Med Biol, 2017 Dec 25; 1036. PMID: 29275467    Free PMC article.
ImmTAC/Anti-PD-1 antibody combination to enhance killing of cancer cells by reversing regulatory T-cell-mediated immunosuppression.
Huanling Zhang, Yanyan Li, +9 authors, Yi Li.
Immunology, 2018 May 24; 155(2). PMID: 29791021    Free PMC article.
Emerging Functions of Regulatory T Cells in Tissue Homeostasis.
Amit Sharma, Dipayan Rudra.
Front Immunol, 2018 Jun 12; 9. PMID: 29887862    Free PMC article.
Highly Cited. Review.
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.
CD226 opposes TIGIT to disrupt Tregs in melanoma.
Julien Fourcade, Zhaojun Sun, +11 authors, Hassane M Zarour.
JCI Insight, 2018 Jul 27; 3(14). PMID: 30046006    Free PMC article.
Treg Fragility: A Prerequisite for Effective Antitumor Immunity?
Abigail E Overacre-Delgoffe, Dario A A Vignali.
Cancer Immunol Res, 2018 Aug 03; 6(8). PMID: 30068755    Free PMC article.
A novel human IL-2 mutein with minimal systemic toxicity exerts greater antitumor efficacy than wild-type IL-2.
Xi Chen, Xiaojie Ai, +4 authors, Gentao Liu.
Cell Death Dis, 2018 Sep 27; 9(10). PMID: 30250191    Free PMC article.
Adoptive Transfers of CD4+CD25+ Tregs Raise Foxp3 Expression and Alleviate Mouse Enteritis.
Kai Wang, Tongjia Zhu, +5 authors, Guixue Hu.
Biomed Res Int, 2018 Oct 27; 2018. PMID: 30364052    Free PMC article.
Tumor-infiltrating regulatory T cells: origins and features.
Guoping Deng.
Am J Clin Exp Immunol, 2018 Dec 01; 7(5). PMID: 30498624    Free PMC article.
Foxp3 Post-translational Modifications and Treg Suppressive Activity.
Guoping Deng, Xiaomin Song, +3 authors, Mark I Greene.
Front Immunol, 2019 Nov 05; 10. PMID: 31681337    Free PMC article.
Treg programming and therapeutic reprogramming in cancer.
Mariela A Moreno Ayala, Zehui Li, Michel DuPage.
Immunology, 2019 Mar 14; 157(3). PMID: 30866047    Free PMC article.
Epigenetic control of Foxp3 in intratumoral T-cells regulates growth of hepatocellular carcinoma.
Qin Liu, Fang Du, +4 authors, Zhiyuan Wu.
Aging (Albany NY), 2019 Apr 23; 11(8). PMID: 31006654    Free PMC article.
Intratumoral regulatory T cells: markers, subsets and their impact on anti-tumor immunity.
Hiroshi Yano, Lawrence P Andrews, Creg J Workman, Dario A A Vignali.
Immunology, 2019 May 16; 157(3). PMID: 31087644    Free PMC article.
Highly Cited. Review.
[Correlations between the T helper cell 17/regulatory T cells balance in peripheral blood of patients with oral lichen planus and clinical characteristics].
Pei-Ru Jia, Yun-Ying Huang, Ying Wang, Yang Cai.
Hua Xi Kou Qiang Yi Xue Za Zhi, 2018 Sep 06; 36(4). PMID: 30182565    Free PMC article.
Epigenetic strategies synergize with PD-L1/PD-1 targeted cancer immunotherapies to enhance antitumor responses.
Xi Chen, Xiaohui Pan, +5 authors, Ling Ding.
Acta Pharm Sin B, 2020 Jun 13; 10(5). PMID: 32528824    Free PMC article.
Targeting Regulatory T Cells for Transplant Tolerance: New Insights and Future Perspectives.
Eman Shaban, George Bayliss, +5 authors, Rujun Gong.
Kidney Dis (Basel), 2018 Dec 24; 4(4). PMID: 30574497    Free PMC article.
Regulatory T cell phenotype and anti-osteoclastogenic function in experimental periodontitis.
Carla Alvarez, Salwa Suliman, +6 authors, Alpdogan Kantarci.
Sci Rep, 2020 Nov 06; 10(1). PMID: 33149125    Free PMC article.
Metabolic profiles of regulatory T cells in the tumour microenvironment.
Disha Rao, Fabienne Verburg, +3 authors, Christian U Blank.
Cancer Immunol Immunother, 2021 Feb 13; 70(9). PMID: 33576875
Tackling tumor microenvironment through epigenetic tools to improve cancer immunotherapy.
Iris Lodewijk, Sandra P Nunes, +3 authors, Jesús M Paramio.
Clin Epigenetics, 2021 Mar 26; 13(1). PMID: 33761971    Free PMC article.
Targeting the epigenetic regulation of antitumour immunity.
Simon J Hogg, Paul A Beavis, Mark A Dawson, Ricky W Johnstone.
Nat Rev Drug Discov, 2020 Sep 16; 19(11). PMID: 32929243
Treg: A Promising Immunotherapeutic Target in Oral Diseases.
Yujing Zhang, Jihua Guo, Rong Jia.
Front Immunol, 2021 Jun 29; 12. PMID: 34177907    Free PMC article.
Epigenetic Reprogramming of CD4+ Helper T Cells as a Strategy to Improve Anticancer Immunotherapy.
Elodie Renaude, Marie Kroemer, +4 authors, Olivier Adotévi.
Front Immunol, 2021 Jul 16; 12. PMID: 34262562    Free PMC article.
Regulatory T Cells-Related Genes Are under DNA Methylation Influence.
Magdalena Piotrowska, Mateusz Gliwiński, Piotr Trzonkowski, Dorota Iwaszkiewicz-Grzes.
Int J Mol Sci, 2021 Jul 21; 22(13). PMID: 34281195    Free PMC article.