Protean Role of Epigenetic Mechanisms and Their Impact in Regulating the Tregs in TME

Overview

Journal Cancer Gene Ther

Specialties Genetics
Oncology
Pharmacology

Date 2021 Jul 29

PMID 34321625

Citations 4

Authors

A S Smiline Girija

Affiliations

Soon will be listed here.

Abstract

Constitutive expression of Foxp3+ Tregs in the tumor microenvironment (TME) specifically renders immune suppression in the tumor tissues. Being highly stable and self-tolerant, Tregs may be influenced by various epigenetic-associated mechanisms while exhibiting their functions. DNA methylation, histone acetylation, epigenetic silencing, alteration in chromatin networks, etc., are some of the main factors underlying the epigenetic-based Treg cell functional modulations in the TME. The possible reasons on why these epigenetic modulations should be specifically targeted are thus discussed, so that enhanced anti-tumor immunity in TME can be achieved.

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References

Liyanage U, Moore T, Joo H, Tanaka Y, Herrmann V, Doherty G . Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002; 169(5):2756-61. DOI: 10.4049/jimmunol.169.5.2756. View

Khattri R, Cox T, Yasayko S, Ramsdell F . An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003; 4(4):337-42. DOI: 10.1038/ni909. View

Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D . Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol. 2008; 27(2):186-92. DOI: 10.1200/JCO.2008.18.7229. View

Ormandy L, Hillemann T, Wedemeyer H, Manns M, Greten T, Korangy F . Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res. 2005; 65(6):2457-64. DOI: 10.1158/0008-5472.CAN-04-3232. View

Siddiqui S, Frigola X, Bonne-Annee S, Mercader M, Kuntz S, Krambeck A . Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma. Clin Cancer Res. 2007; 13(7):2075-81. DOI: 10.1158/1078-0432.CCR-06-2139. View

Heimberger A, Abou-Ghazal M, Reina-Ortiz C, Yang D, Sun W, Qiao W . Incidence and prognostic impact of FoxP3+ regulatory T cells in human gliomas. Clin Cancer Res. 2008; 14(16):5166-72. DOI: 10.1158/1078-0432.CCR-08-0320. View

Matkowski R, Gisterek I, Halon A, Lacko A, Szewczyk K, Staszek U . The prognostic role of tumor-infiltrating CD4 and CD8 T lymphocytes in breast cancer. Anticancer Res. 2009; 29(7):2445-51. View

Walker L . Treg and CTLA-4: two intertwining pathways to immune tolerance. J Autoimmun. 2013; 45:49-57. PMC: 3989116. DOI: 10.1016/j.jaut.2013.06.006. View

Curtin J, Candolfi M, Fakhouri T, Liu C, Alden A, Edwards M . Treg depletion inhibits efficacy of cancer immunotherapy: implications for clinical trials. PLoS One. 2008; 3(4):e1983. PMC: 2291560. DOI: 10.1371/journal.pone.0001983. View

10.

Devaud C, Westwood J, Teng M, John L, Yong C, Duong C . Differential potency of regulatory T cell-mediated immunosuppression in kidney tumors compared to subcutaneous tumors. Oncoimmunology. 2015; 3(11):e963395. PMC: 4368122. DOI: 10.4161/21624011.2014.963395. View

11.

Tanaka A, Sakaguchi S . Regulatory T cells in cancer immunotherapy. Cell Res. 2016; 27(1):109-118. PMC: 5223231. DOI: 10.1038/cr.2016.151. View

12.

Huehn J, Polansky J, Hamann A . Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage?. Nat Rev Immunol. 2008; 9(2):83-9. DOI: 10.1038/nri2474. View

13.

Zheng Y, Josefowicz S, Chaudhry A, Peng X, Forbush K, Rudensky A . Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature. 2010; 463(7282):808-12. PMC: 2884187. DOI: 10.1038/nature08750. View

14.

Josefowicz S, Niec R, Kim H, Treuting P, Chinen T, Zheng Y . Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature. 2012; 482(7385):395-9. PMC: 3485072. DOI: 10.1038/nature10772. View

15.

Toker A, Engelbert D, Garg G, Polansky J, Floess S, Miyao T . Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus. J Immunol. 2013; 190(7):3180-8. DOI: 10.4049/jimmunol.1203473. View

16.

Ehrlich M, Gama-Sosa M, Huang L, Midgett R, KUO K, McCune R . Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells. Nucleic Acids Res. 1982; 10(8):2709-21. PMC: 320645. DOI: 10.1093/nar/10.8.2709. View

17.

Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y . T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity. 2012; 37(5):785-99. DOI: 10.1016/j.immuni.2012.09.010. View

18.

Schmidl C, Klug M, Boeld T, Andreesen R, Hoffmann P, Edinger M . Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res. 2009; 19(7):1165-74. PMC: 2704427. DOI: 10.1101/gr.091470.109. View

19.

Feng Y, van der Veeken J, Shugay M, Putintseva E, Osmanbeyoglu H, Dikiy S . A mechanism for expansion of regulatory T-cell repertoire and its role in self-tolerance. Nature. 2015; 528(7580):132-136. PMC: 4862833. DOI: 10.1038/nature16141. View

20.

Kitagawa Y, Ohkura N, Kidani Y, Vandenbon A, Hirota K, Kawakami R . Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. Nat Immunol. 2016; 18(2):173-183. PMC: 5582804. DOI: 10.1038/ni.3646. View