T Regulatory Cells and Priming the Suppressive Tumor Microenvironment

doi:10.3389/fimmu.2019.02453

Review

. 2019 Oct 15:10:2453.

doi: 10.3389/fimmu.2019.02453. eCollection 2019.

T Regulatory Cells and Priming the Suppressive Tumor Microenvironment

Christina M Paluskievicz¹, Xuefang Cao², Reza Abdi³, Pan Zheng^{1

4}, Yang Liu^{1

4}, Jonathan S Bromberg^{1

2

5}

Affiliations

¹ Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States.
² Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States.
³ Division of Renal Medicine, Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
⁴ Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States.
⁵ Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, United States.

PMID: 31681327
PMCID: PMC6803384
DOI: 10.3389/fimmu.2019.02453

Review

T Regulatory Cells and Priming the Suppressive Tumor Microenvironment

Christina M Paluskievicz et al. Front Immunol. 2019.

. 2019 Oct 15:10:2453.

doi: 10.3389/fimmu.2019.02453. eCollection 2019.

Authors

Christina M Paluskievicz¹, Xuefang Cao², Reza Abdi³, Pan Zheng^{1

4}, Yang Liu^{1

4}, Jonathan S Bromberg^{1

2

5}

Affiliations

¹ Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States.
² Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States.
³ Division of Renal Medicine, Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
⁴ Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States.
⁵ Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, United States.

PMID: 31681327
PMCID: PMC6803384
DOI: 10.3389/fimmu.2019.02453

Abstract

Treg play a central role in maintenance of self tolerance and homeostasis through suppression of self-reactive T cell populations. In addition to that role, Treg also survey cancers and suppress anti-tumor immune responses. Thus, understanding the unique attributes of Treg-tumor interactions may permit control of this pathologic suppression without interfering with homeostatic self-tolerance. This review will define the unique role of Treg in cancer growth, and the ways by which Treg inhibit a robust anti-tumor immune response. There will be specific focus placed on Treg homing to the tumor microenvironment (TME), TME formation of induced Treg (iTreg), mechanisms of suppression that underpin cancer immune escape, and trophic nonimmunologic effects of Treg on tumor cells.

Keywords: Treg; anti-tumor immunity; immunosuppression; metastasis; tumor microenvironment.

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Figures

**Figure 1**
Tumor cell and Treg homing interactions. Treg home to the TME through interactions with chemokines/ligands produced by TME components including cancer cells. Some interactions are depicted including S1P:S1PR, CXCL12:CXCR4, CCL20:CCR6, CCL5:CCR5, CCL28:CCR10, and CCL2/22:CCR4.

**Figure 2**
Mechanisms of iTreg induction in the TME. iTreg are derived from naïve CD4+ T cells following exposure to a specific cytokine milieu. Constituents of the TME are capable of producing several factors that form iTreg which further promote immunosuppression and inhibition of the anti-tumor immune response. Specific factors that drive the formation of iTreg include TGFβ and IL-10; TGFβ and IL-10 transcripts have been isolated from tumor subtypes including ovarian, breast, renal cell, lung, and squamous cell carcinoma. Tumor derived exosomes contain IL-10, TGFβ, and Fas ligand capable of generating iTreg. IDO1 is ubiquitously expressed by components of the TME, including tumor cells, stromal cells, DCs, and MDSCs which drive induction of iTreg. Binding of tumor derived PD-L1/L2 to T cell PD-1 is implicated in development, maintenance, and suppressive function of iTreg through stabilization of FoxP3 expression.

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References

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1. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. (2003) 299:1057–62. 10.1126/science.1079490 - DOI - PubMed
1. Pacholczyk R, Kern J. The T-cell receptor repertoire of regulatory T cells. Immunology. (2008) 125:450–8. 10.1111/j.1365-2567.2008.02992.x - DOI - PMC - PubMed
1. Shitara K, Nishikawa H. Regulatory T cells: a potential target in cancer immunotherapy. Ann NY Acad Sci. (2018) 1417:104–15. 10.1111/nyas.13625 - DOI - PubMed
1. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, et al. . Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3 + T regulatory cells. J Immunol. (2010) 184:3433–41. 10.4049/jimmunol.0904028 - DOI - PMC - PubMed

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[1] Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4 + CD25 + T regulatory cells. Nat Immunol. (2003) 4:337–42. 10.1038/ni909 - DOI - PubMed

[2] Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4 + CD25 + T regulatory cells. Nat Immunol. (2003) 4:337–42. 10.1038/ni909 - DOI - PubMed

[3] Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. (2003) 299:1057–62. 10.1126/science.1079490 - DOI - PubMed

[4] Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. (2003) 299:1057–62. 10.1126/science.1079490 - DOI - PubMed

[5] Pacholczyk R, Kern J. The T-cell receptor repertoire of regulatory T cells. Immunology. (2008) 125:450–8. 10.1111/j.1365-2567.2008.02992.x - DOI - PMC - PubMed

[6] Pacholczyk R, Kern J. The T-cell receptor repertoire of regulatory T cells. Immunology. (2008) 125:450–8. 10.1111/j.1365-2567.2008.02992.x - DOI - PMC - PubMed

[7] Shitara K, Nishikawa H. Regulatory T cells: a potential target in cancer immunotherapy. Ann NY Acad Sci. (2018) 1417:104–15. 10.1111/nyas.13625 - DOI - PubMed

[8] Shitara K, Nishikawa H. Regulatory T cells: a potential target in cancer immunotherapy. Ann NY Acad Sci. (2018) 1417:104–15. 10.1111/nyas.13625 - DOI - PubMed

[9] Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, et al. . Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3 + T regulatory cells. J Immunol. (2010) 184:3433–41. 10.4049/jimmunol.0904028 - DOI - PMC - PubMed

[10] Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, et al. . Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3 + T regulatory cells. J Immunol. (2010) 184:3433–41. 10.4049/jimmunol.0904028 - DOI - PMC - PubMed

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T Regulatory Cells and Priming the Suppressive Tumor Microenvironment

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T Regulatory Cells and Priming the Suppressive Tumor Microenvironment

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