Regulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy

Jung-Ho Kim; Beom Seok Kim; Sang-Kyou Lee

doi:10.4110/in.2020.20.e4

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Kim, Kim, and Lee: Regulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy

Review Article

Immune Netw 2020;20(1):e4.

Published online: 4 February 2020

DOI: https://doi.org/10.4110/in.2020.20.e4

Regulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy

Jung-Ho Kim¹, Beom Seok Kim¹, Sang-Kyou Lee^1,^2,^*

¹Research Institute for Precision Immune-Medicine, Good T Cells, Inc., Seoul 03722, Korea

²Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea

^*Correspondence to Sang-Kyou Lee Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University and Research Institute for Precision Immune-Medicine, Good T Cells, Inc., 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. E-mail: sjrlee@yonsei.ac.kr

Conflict of Interest The authors declare no potential conflicts of interest.

Received 19 January 2020 Revised 30 January 2020 Accepted 2 February 2020

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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

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Figure 1.

Classification of human CD4⁺ FOXP3⁺ T cells. In humans, CD4⁺ FOXP3⁺ T cells can be classified into three subsets: naïve Tregs (Fr.1), eTregs (Fr.2), and non-Tregs (Fr.3). These three fractions can be distinguished based on the expression of CD45RA, cell surface markers of naive T cells, and the transcription factor FOXP3. Moreover, these subpopulations are functionally different in terms of their suppressive activity. Effector Tregs harbor strong immune suppressive activity, but non-Tregs do not possess immune suppressive activity. In the majority of cancer, eTregs predominantly infiltrate into tumor tissues. In general, the frequency of eTregs in cancer patients is 2∼5% in peripheral blood but approximately 10∼50% in the tumor tissues. In contrast, naïve Tregs and FOXP3⁺ non-Tregs are insufficient or absent altogether.

Figure 2.

Role of Tregs in immune-evasion of cancer after differentiation from the thymus. Natural Tregs, generated in the thymus, are initially differentiated from the thymocytes by using thymic “positive selection” based on the binding affinity of TCR to the self- peptides-MHC complexes expressed on thymic APCs. The CD4⁺ T cells which bind to self-peptide-MHC complexes with the highest affinity are removed through apoptosis, and those that cannot bind at all with the complexes will also be removed because of the absence of TCR stimulation. After strong TCR stimulation, these immature precursor cells undergo IL-2-mediated signaling, thus expressing the master transcription factor FOXP3, which orchestrates the differentiation of these cells into Tregs. By contrast, immature T cells with lower affinity for self-peptide–MHC complexes are also positively selected but differentiate into Teff cells. Even though some Teff cells are auto-reactive, Tregs can block the autoimmunity of Teff cells owing to their higher affinity. These immune cells that have departed from the thymus travel through the blood vessels and move wherever they are needed. In the tumor microenvironment, especially, Tregs expressing the chemokine receptors, such as CCR4, CCR5, CCR8, and CCR10, are recruited to and around the tumors by binding to chemokines including CCL1, CCL5, CCL22, and CCL28 that are secreted from various kinds of tumors. Moreover, Tregs constitutively express the IL-2 receptor subunit-α (also known as CD25) that binds to IL-2 with higher affinity, resulting in the depletion of IL-2 from their surroundings. This leads to the reduction of the availability of this cytokine to Teff cells. Tregs also constitutively express CTLA-4, a checkpoint protein suppressing the immune response, which binds to CD80 and CD86 on APC, thereby transmitting suppressive signals to Teff cells. In addition, Tregs secrete cytokines, such as IL-10, IL-35, and TGF-β, which can decrease the activity of APCs and Teff cells and secrete granzymes and perforins that can directly kill these cells. Moreover, abundant adenosine is produced by Tregs via nucleotidase activity of CD39 and CD73, which provides immunosuppressive signals to Teff cells and APCs through the engagement of adenosine A2AR.

Table 1.

Ab-drug development status of Treg-targeting therapy

Treg markers	Representative drugs	Function of Ab	Tumor types	Development stage
CD25	Daclizumab	Depletion	Leukemia/lymphoma	Phase 2
CTLA-4	Ipilimumab	Antagonist	Melanoma	Commercialized
PD-1	Nivolumab	Antagonist	Melanoma, lymphoma	Commercialized
GITR	TRX518	Agonist	Melanoma	Phase 1
CCR4	Mogamulizumab	Antagonist	CCR4⁺ adult T-cell leukemia/lymphoma	Commercialized
OX40	PF-04518600	Agonist	Advanced malignant cancer	Phase 2
ICOS	JTX-2011	Agonist	Advanced/refractory solid cancer	Phase 1/2
LAG3	Sym-2011	Antagonist	Solid tumor, lymphoma	Phase 1
TIM-3	Sym-023	Antagonist	Solid tumor, lymphoma	Phase 1
TIGIT	BMS-986207	Antagonist	Multiple myeloma	Phase 1/2

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