Emerging roles of regulatory T cells in tumour progression and metastasis

Abstract

The metastasis of cancer is a complex and life-threatening process that is only partially understood. Immune suppressive cells are recognized as important contributors to tumour progression and may also promote the development and growth of tumour metastases. Specifically, regulatory T cells (Tregs) have been found to promote primary tumour progression, and emerging pre-clinical data suggests that Tregs may promote metastasis and metastatic tumour growth. While the precise role that Tregs play in metastatic progression is understudied, recent findings have indicated that by suppressing innate and adaptive anti-tumour immunity, Tregs may shield tumour cells from immune detection, and thereby allow tumour cells to survive, proliferate and acquire characteristics that facilitate dissemination. This review will highlight our current understanding of Tregs in metastasis, including an overview of pre-clinical findings and discussion of clinical data regarding Tregs and therapeutic outcome. Evolving strategies to directly ablate Tregs or to inhibit their function will also be discussed. Improving our understanding of how Tregs may influence tumour metastasis may lead to novel treatments for metastatic cancer.

Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis

“…Although not definitive, these cells are generally characterized as CD4 + CD25 high , and express the master regulatory transcription factor FoxP3 [57]. Tregs can induce immunosuppression through contact-dependent mechanisms such as the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), lymphocyte-activation protein 3 (LAG-3), CD39/73 and neuropilin 1 (Nrp1), or through contact-independent mechanisms, including the sequestration of IL-2 and the production of the soluble immunosuppressive molecules IL-10, TGF-β, adenosine, prostaglandin E 2 (PGE 2 ) or galectin-1 [52, 55, 58–61] (Fig. 3a).…”

“…Emerging evidence suggests that Tregs promote metastasis and metastatic tumor foci development [52]. A clinical study of NSCLC observed that Treg levels in peripheral blood increased with stage and were highest in patients with metastatic tumors [70].…”

“…Moreover, Th17 differentiation can occur when pro-inflammatory cytokines, including IL-6, IL-21 and IL-23, inhibit FoxP3 expression and subsequent repression of RORγt [48, 50]. In addition to de novo generation of Tregs from FoxP3 − T cells, Tregs can also be generated under homeostatic or pathological conditions via proliferation of thymus-derived FoxP3 + cells [51, 52]. Additionally, a novel mechanism of Treg-dependent promotion of Th17 differentiation via IL-2 sequestration has been shown to promote IL-17-driven inflammation and tumorigenesis in colon cancer, highlighting the complex interplay between these two cell types in the context of cancer [53].…”

Immune responses in the thyroid cancer microenvironment: making immunotherapy a possible mission

“…Regulatory T cells are involved in shutting down immune responses and their presence correlates with disease progression and may encourage metastases to lymph nodes in various cancers (Halvorsen et al 2014). Regulatory T cells are known to be present in papillary thyroid cancers and may be involved in promoting more aggressive disease (French et al 2010).…”

Immunological effects of vaccines combined with granulocyte colony-stimulating factor on a murine WEHI-3 leukemia model

“…Cluster of differentiation (CD)4 + /CD25 + /forkhead box protein P3 (Foxp3 + ) regulatory T cells (Tregs) are a subpopulation of T cells with a suppressive activity on immune responses (9). Tregs that exist in the AML microenvironment (10), and other cancer bearing individuals, (11–14) are mediators of immune suppression.…”