. 2020 Mar; 20(1):e4.
doi: 10.4110/in.2020.20.e4.

Regulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy

Jung-Ho Kim 1 Beom Seok Kim 1 Sang-Kyou Lee 1 
  • PMID: 32158592
  •     118 References
  •     15 citations


Tregs have a role in immunological tolerance and immune homeostasis by suppressing immune reactions, and its therapeutic potential is critical in autoimmune diseases and cancers. There have been multiple studies conducted on Tregs because of their roles in immune suppression and therapeutic potential. In tumor immunity, Tregs can promote the development and progression of tumors by preventing effective anti-tumor immune responses in tumor-bearing hosts. High infiltration of Tregs into tumor tissue results in poor survival in various types of cancer patients. Identifying factors specifically expressed in Tregs that affect the maintenance of stability and function of Tregs is important for understanding cancer pathogenesis and identifying therapeutic targets. Thus, manipulation of Tregs is a promising anticancer strategy, but finding markers for Treg-specific depletion and controlling these cells require fine-tuning and further research. Here, we discuss the role of Tregs in cancer and the development of Treg-targeted therapies to promote cancer immunotherapy.

Keywords: Immunotherapy; T-lymphocytes, regulatory (Treg cells); Tumor microenvironment.

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J Immunol, 2001 Jul 24; 167(3). PMID: 11466340
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Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells.
Stefani Spranger, Robbert M Spaapen, +4 authors, Thomas F Gajewski.
Sci Transl Med, 2013 Aug 30; 5(200). PMID: 23986400    Free PMC article.
Highly Cited.
Tim-3 and its role in regulating anti-tumor immunity.
Madhumita Das, Chen Zhu, Vijay K Kuchroo.
Immunol Rev, 2017 Mar 05; 276(1). PMID: 28258697    Free PMC article.
Highly Cited. Review.
Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory.
Luigia Pace, Andy Tempez, +5 authors, Sebastian Amigorena.
Science, 2012 Nov 01; 338(6106). PMID: 23112334
Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8+ T cells in the tumor microenvironment.
Yasuko Tada, Yosuke Togashi, +7 authors, Kohei Shitara.
J Immunother Cancer, 2018 Oct 14; 6(1). PMID: 30314524    Free PMC article.
Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement.
V L Perez, L Van Parijs, +3 authors, A K Abbas.
Immunity, 1997 Apr 01; 6(4). PMID: 9133420
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VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors.
Thibault Voron, Orianne Colussi, +15 authors, Magali Terme.
J Exp Med, 2015 Jan 21; 212(2). PMID: 25601652    Free PMC article.
Highly Cited.
Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses.
Sharad Shrestha, Kai Yang, +3 authors, Hongbo Chi.
Nat Immunol, 2015 Jan 07; 16(2). PMID: 25559258    Free PMC article.
Highly Cited.
Tumor immunotherapy directed at PD-1.
Antoni Ribas.
N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658126
Highly Cited.
Clinical experience with denileukin diftitox (ONTAK).
Francine Foss.
Semin Oncol, 2006 Mar 07; 33(1 Suppl 3). PMID: 16516670
Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer.
Sylvain Ladoire, François Martin, François Ghiringhelli.
Cancer Immunol Immunother, 2011 Jun 07; 60(7). PMID: 21644034
Highly Cited. Review.
Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase.
Catherine Uyttenhove, Luc Pilotte, +5 authors, Benoît J Van den Eynde.
Nat Med, 2003 Sep 23; 9(10). PMID: 14502282
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Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor.
Makoto Miyara, Yumiko Yoshioka, +15 authors, Shimon Sakaguchi.
Immunity, 2009 May 26; 30(6). PMID: 19464196
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Coalition Forces of Immunologists and Oncologists for Defeating Cancer.
Eui-Cheol Shin.
Immune Netw, 2020 Mar 12; 20(1). PMID: 32158589    Free PMC article.
The Resistance Mechanisms of Checkpoint Inhibitors in Solid Tumors.
Evangelos Koustas, Panagiotis Sarantis, Athanasios G Papavassiliou, Michalis V Karamouzis.
Biomolecules, 2020 Apr 30; 10(5). PMID: 32344837    Free PMC article.
Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy.
Wei Liu, Paweł Stachura, +4 authors, Aleksandra A Pandyra.
Cancers (Basel), 2020 Oct 04; 12(10). PMID: 33008037    Free PMC article.
Molecular Immunotherapy: Promising Approach to Treat Metastatic Colorectal Cancer by Targeting Resistant Cancer Cells or Cancer Stem Cells.
Stefan Forster, Ramin Radpour.
Front Oncol, 2020 Nov 27; 10. PMID: 33240813    Free PMC article.
Immunotherapy in Solid Tumors and Gut Microbiota: The Correlation-A Special Reference to Colorectal Cancer.
Asimina Koulouridi, Ippokratis Messaritakis, +2 authors, John Souglakos.
Cancers (Basel), 2020 Dec 31; 13(1). PMID: 33375686    Free PMC article.
Polyvinyl Alcohol Carbazate as a Polymer-Based Antitumoral Agent.
Felix Sellberg, Robin Fröbom, +2 authors, David Berglund.
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Inflammation-Driven Breast Tumor Cell Plasticity: Stemness/EMT, Therapy Resistance and Dormancy.
Tamir Baram, Linor Rubinstein-Achiasaf, Hagar Ben-Yaakov, Adit Ben-Baruch.
Front Oncol, 2021 Feb 16; 10. PMID: 33585241    Free PMC article.
Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy.
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Expression and clinicopathological significance of Foxp3 and VISTA in cervical cancer.
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[Peripheral Blood Inflammation Indicators as Predictive Indicators in 
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Regulatory T Cells: Regulation of Identity and Function.
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Nature vs. Nurture: The Two Opposing Behaviors of Cytotoxic T Lymphocytes in the Tumor Microenvironment.
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Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: limitations and prospects: a systematic review.
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Clinical perspectives on the age-related increase of immunosuppressive activity.
Antero Salminen.
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Immune Landscape in PTEN-Related Glioma Microenvironment: A Bioinformatic Analysis.
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