Received: 29 August 2018 | Accepted: 13 September 2018 DOI: 10.1002/jcp.27553 REVIEW ARTICLE Contribution of regulatory T cells to cancer: A review Masoud Najafi 1 | Bagher Farhood 2 | Keywan Mortezaee 3 1 Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran 2 Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran 3 Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran Correspondence Keywan Mortezaee, Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj 66177‐13446, Iran. Email: keywan987@yahoo.com; mortezaee.k@muk.ac.ir Abstract Regulatory T cells (Tregs) represent a low number of T‐cell population under normal conditions, and they play key roles for maintaining immune system in homeostasis. The number of these cells is extensively increased in nearly all cancers, which is for dampening responses from immune system against cancer cells, metastasis, tumor recurrence, and treatment resistance. The interesting point is that apoptotic Tregs are stronger than their live counterparts for suppressing responses from immune system. Tregs within the tumor microenvironment have extensive positive cross‐talks with other immunosuppressive cells including cancer‐associated fibroblasts, cancer cells, macrophage type 2 cells, and myeloid‐derived suppressor cells, and they have negative interactions with immunostimulatory cells including cytotoxic T lymphocytes (CTL) and natural killer cells. A wide variety of markers are expressed in Tregs, among them forkhead box P3 (FOXP3) is the most specific marker and the master regulator of these cells. Multiple signals are activated by Tregs including transforming growth factor‐β, signal transducer and activator of transcription, and mTORC1. Treg reprogramming from an immunosuppressive to immunostimulatory proinflammatory phenotype is critical for increasing the efficacy of immunotherapy. This would be applicable through selective suppression of tumor‐bearing receptors in Tregs, including FOXP3, programmed death‐1, T‐cell immunoglobulin mucin‐3, and CTL‐ associated antigen‐4, among others. Intratumoral Tregs can also be targeted by increasing the ratio for CTL/Treg. KEYWORDS cancer cell, cyclooxygenase‐2, forkhead box P3, immunosuppression, PD‐1, regulatory T cell, signal transducer and activator of transcription, transforming growth factor‐β, tumor microenvironment 1 | INTRODUCTION Tumor microenvironment (TME) is a host for nurturing complex network of heterogeneous stromal cells with either overlapping or opposing functions depending on the dominant signals within this milieu. Regulatory T cells (Tregs) are identified as immunosuppressive subset of CD4 + T cells (D. Wang, Quiros, et al., 2018a) that represent about 4–5% of the whole CD4 + T‐cell population in normal conditions (Mougiakakos et al., 2010), and they work for preserving immune tolerance and suppressing autoimmune diseases (D. Wang, Quiros, et al., 2018a). Tregs are identified as the prevailing T‐cell responders to the early tumors outpacing cytotoxic T lymphocytes (CTLs) during early tumor growth (Shabaneh et al., 2018). To maintain immune system in homeostasis, there is a tight regulation over Treg development (Y. Liu, Zhang, et al., 2018). However, presence of these cells in tumor tissues could impair antitumor immunity and so portends worse prognoses in affected patients (D. Wang, Quiros, et al., 2018a). The poor prognostic feature related to Treg presence in tumor patient has made the cells a subject of intensive basic and clinical research over the past 5 years (Mougiakakos et al., 2010). J Cell Physiol. 2018;1–11. wileyonlinelibrary.com/journal/jcp © 2018 Wiley Periodicals, Inc. | 1