Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target?

• Published in: Cancer science Vol. 110; no. 7; pp. 2080 - 2089
• Main Authors: Ohue, Yoshihiro, Nishikawa, Hiroyoshi
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.07.2019; John Wiley and Sons Inc
• Subjects: Adenosine; Animals; Antigens; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Antitumor activity; Autoantigens; Autoimmune diseases; Autoimmunity; Cancer; Cancer immunotherapy; CCL17 protein; CCR8 protein; CD25 antigen; CD80 antigen; CD86 antigen; Chemokine receptors; Chemokines; CTLA-4 Antigen - metabolism; CXCR3 protein; Cytokines; Cytokines - metabolism; Cytotoxicity; Dendritic cells; Effector cells; Homeostasis; Humans; Immune checkpoint; immune suppression; Immunoregulation; Immunotherapy; Immunotherapy - methods; Interleukin-2 - metabolism; Interleukin-2 Receptor alpha Subunit - metabolism; Lymphocytes; Lymphocytes T; Metabolism; Metabolites; Metastases; Mice; Neoplasms - drug therapy; Neoplasms - immunology; Patients; Precision medicine; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Review; Small Molecule Libraries - pharmacology; Small Molecule Libraries - therapeutic use; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Therapeutic applications; tolerance; Treg; tumor; Tumor necrosis factor-TNF; Vascular endothelial growth factor; immune suppression; tumor; tolerance; Treg; immune checkpoint
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.14069

Regulatory T (Treg) cells suppress abnormal/excessive immune responses to self‐ and nonself‐antigens to maintain immune homeostasis. In tumor immunity, Treg cells are involved in tumor development and progression by inhibiting antitumor immunity. There are several Treg cell immune suppressive mechanisms: inhibition of costimulatory signals by CD80 and CD86 expressed by dendritic cells through cytotoxic T‐lymphocyte antigen‐4, interleukin (IL)‐2 consumption by high‐affinity IL‐2 receptors with high CD25 (IL‐2 receptor α‐chain) expression, secretion of inhibitory cytokines, metabolic modulation of tryptophan and adenosine, and direct killing of effector T cells. Infiltration of Treg cells into the tumor microenvironment (TME) occurs in multiple murine and human tumors. Regulatory T cells are chemoattracted to the TME by chemokine gradients such as CCR4‐CCL17/22, CCR8‐CCL1, CCR10‐CCL28, and CXCR3‐CCL9/10/11. Regulatory T cells are then activated and inhibit antitumor immune responses. A high infiltration by Treg cells is associated with poor survival in various types of cancer. Therefore, strategies to deplete Treg cells and control of Treg cell functions to increase antitumor immune responses are urgently required in the cancer immunotherapy field. Various molecules that are highly expressed by Treg cells, such as immune checkpoint molecules, chemokine receptors, and metabolites, have been targeted by Abs or small molecules, but additional strategies are needed to fine‐tune and optimize for augmenting antitumor effects restricted in the TME while avoiding systemic autoimmunity. Here, we provide a brief synopsis of these cells in cancer and how they can be controlled to achieve therapeutic outcomes. Regulatory T cells suppress immune functions through various mechanisms such as cytotoxic T‐lymphocyte antigen‐4‐mediated suppression of antigen‐presenting cell function, consumption of interleukin‐2, production of immunosuppressive cytokines, and production of immune suppressive metabolites.