Phenotypic and Functional Properties of Tumor-Infiltrating Regulatory T Cells

Received Oct 31, 2017; Revised Dec 11, 2017; Accepted Dec 12, 2017

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1. Introduction

Regulatory T (Treg) cells are CD4 T cells that inhibit immune responses. Treg cells express high amounts of CD25 and transcription factor Forkhead box protein 3 (Foxp3) [1, 2]. Treg cells maintain immune homeostasis by inhibiting immune responses. These cells not only protect tissues from excessive immune responses but also suppress immune responses against self-antigens, innocuous environmental antigens, antigens from food and microbiota, and fetal antigens during pregnancy.

Treg cells inhibit immune responses by a variety of mechanisms, including the secretion of anti-inflammatory cytokines such as interleukin- (IL-) 10, tumor growth factor- (TGF-) β, and IL-35 [3]. In addition, Treg cells express high levels of IL-2R, depleting IL-2, a growth factor for effector T (Teff) cells, in the surrounding environment. Treg cells also kill Teff cells directly through the FasL-Fas pathway as well as through granzyme-/perforin-mediated cytotoxicity, disrupting the metabolism of Teff cells. Moreover, Treg cells can suppress immune responses by inducing tolerogenic dendritic cells (DCs) [3].

Two types of Treg cells have been identified. Thymus-derived Treg (tTreg) cells develop in the thymus, whereas periphery-derived Treg (pTreg) cells differentiate from naive CD4 T cells in the periphery.

Incipient tumor cells are removed by immune system cells; specifically, CD8⁺ cytotoxic T lymphocytes (CTLs) kill tumor cells, aided by CD4⁺ T cells. Tumor cells express tumor-associated antigens (TAAs), which are newly expressed or mutated self-antigens, and are recognized and killed by CTLs, a phenomenon known as “cancer immune surveillance.” Continual generation of cancer cells and removal by immune cells can be balanced and can last for a long time. Some of these cancer cells may eventually evade immune responses and grow unchecked. Thus, immune system cells are critical in keeping cancers under control.

Treg cells infiltrate tumors and inhibit antitumor immune responses by tumor antigen-specific CD8 T cells and CD4 T cells. Thus, Treg...