Essay on Characteristics Of Treg Cells
Regulatory T (Treg) cells help maintain immune homeostasis by suppressing atypical and excessive immune responses to self and nonself antigens. Tregs can inhibit anti-tumour immune responses and lead to the establishment of an immunosuppressive tumour microenvironment (TME), thus facilitating cancer progression (Li et al., 2020). Tregs can be induced and differentiated in the tumour microenvironment (TME) by conventional T cells, which have a high immunosuppressive role, to block anti-tumor immunity and facilitate the formation of tumours. Sakaguchi et al., (2010) discovered that the forkhead helix transcription factor (Foxp3) was primarily expressed in Tregs, and CD4+, CD25+, Foxp3+ is now thought to be a classical combination of Tregs markers. Although the actual role of Foxp3 is still unclear, this molecule is believed to be a transcription factor. When activated, Foxp3 can function as a repressor of transcription. Additionally, it has been suggested that upon activation, all human CD4+ and CD8+ T cells can upregulate Foxp3 and attain suppressive characteristics (Sakaguchi et al., 2010).
In cancer, Tregs have been found in the peripheral blood and also in the body's immune infiltrates. The build-up of FoxP3+ Tregs and a high Treg: T effector cell (Teff) ratio within the tumour tissue was correlated with a poor prognosis in a variety of cancers, including lung cancer, pancreatic ductal adenocarcinoma, ovarian cancer, non-Hodgkin's lymphoma and glioblastoma (Chaudhary & Elkord, 2016). Tregs promote tumour development through a variety of mechanisms such as secreting TGFβ, IL-10, and IL-35 (Li et al., 2020), all of which suppress antitumor immunity, CD4+ T helper (Th) cells act and produce CD8+ cytotoxic T lymphocytes specific for tumours (CTLs) and inhibit the antigen presentation by tolerogenic DCs dendritic cells (Chaudhary & Elkord, 2016). Hence, this essay will outline some of the processes by which Tregs promote tumour progression (Chaudhary & Elkord, 2016).
Treg cells promote tumour growth via contact independent mechanisms:
- Secretion of immunosuppressive cytokines
TGFβ frequently promotes iTreg activation and tumour progression. Tumours evolve in an autocrine form, secreting growing amounts of TGFβ (Neel et al., 2012). This cytokine is also caused by the thick stromal matrix around the tumour and the infiltrating immune cells. Increased TGFβ in the TME is associated with advanced-stage conditions and worse prognoses (Tang et al., 2003).
IL-10, responsible for self-tolerance, but also inhibits the anti-tumour immune response. IL-10 maintains FoxP3, TGFR, and TGF expression in newly triggered Treg, thus stabilising their inhibiting characteristics (Dennis et al., 2013). Treg was established as a significant source of IL-10 in the TME. For example, a study by Stewart et al., (2013) showed enhanced IL-10 production in CD4+, CD25+ and FoxP3+ intra-tumoral Treg, indicating a strongly active suppressor phenotype. IL-10 levels in the TME and peripheral blood are associated with a weaker prognosis for ovarian cancer, late-stage illness of bowel cancer, and increased tumour size in non-small cell lung cancer (NSCLC) (Stewart et al., 2013).
IL-35 is a cytokine that acts as an inhibitory factor in the TME. The intracellular signalling of IL-35 varies based on the immune cell type, but it is regulated in part by the JAK-STAT pathway, leading to the inhibition of T cell expansion by cell cycle arrest at the G1-S phase (Paluskievicz et al., 2019). Secretion of IL-35 Tregs is more common in stable controls' peripheral blood, TdLNs and TME. Increased plasma levels of IL-35 correspond favourably to increased tumour measures (Jin et al., 2014).
- Competition between growth factors enhances tumour growth
Additionally, TGF and IL-10 work synergistically to enhance the differentiation of human iTreg through elevated FoxP3 and CTLA-4 expression (Hsu et al., 2015). The percentages of FoxP3+ T cells and expression of CTLA-4 is increased when CD4+, CD45RO- and CD25- T cells are exposed to anti-CD3/CD28, IL-2, and TGFβ in the presence of IL-10 (Paluskievicz et al., 2019). Tumour development is induced by the activation of iTreg cells in the TME, and the presence of iTreg cells is negatively correlated with the overall survival rates of some cancer types.
IL-2 is a pro-inflammatory cytokine with a range of TME-specific roles and traits. The IL-2 receptor, otherwise called the CD25, which facilitates the growth and survival of Foxp3+ Treg. Though IL-2 is essential for the survival of Treg, Pandiyan et al., (2007) established that Treg utilizes high-affinity CD25 to displace neighbouring T cells for IL-2, leading to responder T cell apoptosis, a phase termed for IL-2 disintegration. As a result, Treg deprivation of anti-tumour effector IL-2 facilitates tumour responsiveness by limiting the effector T cell response (Paluskievicz et al., 2019).
Treg cells promote tumour growth via cell contact dependent mechanisms
CTLA-4 is an inhibitor of checkpoints that are induced in the T cells after activation; it is expressed by Treg (Baksh & Weber, 2015). Activated protein C (APCs) interfere with cell proliferation, cytokine synthesis, and effector T cell survival pathways by engaging with CTLA-4. CTLA-4 is a homolog of CD28; Treg have a high affinity for CTLA-4, which competitively binds to CD80/86 on APC. This blocks CD28-mediated costimulatory signals, and thus inhibits other co-stimulatory agents necessary for T cell stimulation. For example, in a study, mice were treated with radioactive B16 melanoma cells and controlled by checkpoint signal inhibition, such as anti-CTLA-4, which had a significant reduction in tumour cell stress and an elevated CD4+/CD8+ to Treg proportion in the tumour. As a result, Treg CTLA-4 is a key immunosuppressive agent that tends to facilitate anti-tumour response inhibition (Baksh & Weber, 2015).
Perforin stimulates the development of pores in membranes, enabling the entrance of granzymes A and B into the cytosol and inducing caspase-dependent apoptosis in target cells. According to reports, Tregs transmit perforin and granzyme as a method of immunosuppression. Perforin and granzyme extracted from Tregs specifically attack natural killer (NK) and CD8+ T cells, making them ineffective in killing tumour cells, resulting in tumour growth. Li et al., (2020) examined granzyme B and perforin production in Treg extracted from human breast cancer TME; Treg derived from breast tissue released slightly more granzyme B than Treg isolated from peripheral blood tests of the same individual (Paluskievicz et al., 2019).
Lymphocyte activation gene 3 (LAG-3) is articulated on stimulated T cells, natural killer cells (NK), and B cells that acts as an immune regulating molecule. LAG-3 intracellular signalling and the precise pathways of immunosuppression are still unknown; nevertheless, immunosuppression is most definitely accomplished by LAG-3: MHC II activity, which results in disrupted DC maturation and arresting of tumour infiltrating T cells. Camisaschi et al., (2010) identified a population of CD25+, FoxP3+ and CD4+, T cells expressing LAG-3 that was seen in elevated numbers in the peripheral blood and solid tumours of patients with colorectal cancer. CD4+, CD25+, FoxP3+ and LAG-3 Treg cells exhibit improved inhibiting properties as compared to LAG-3- cells. As CD4+, CD25- T cells and LAG-3+ Treg cells are segregated via membranes, Treg inhibiting characteristics are lost, meaning that the mechanism needs direct cell interaction. Thus, the direct interaction of LAG-3 with MHC II molecules present on a variety of cells in the TME adds another pathway for Treg immunosuppression (Paluskievicz et al., 2019).
The recruitment of Tregs in tumour angiogenesis
Angiogenesis is the process by which new blood vessels develop and is important for tumour growth since it provides essential nutrients and growth factors. When a tumour develops, it attracts a large number of Treg from the body. These cells have been shown to have elevated biomarkers of rapid angiogenesis, such as increased micro vessel density in endometrial and breast cancers and overexpression of VEGF, which means that tumour development leads to an increased propensity for angiogenesis (Facciabene et al., 2012). Indirect and direct pathways of tumour angiogenesis have been discovered in the study of Treg. Th1 effector T cells that release angiogenic cytokines such as IFNγ and TNFα as well as chemokines (interferon-induced) like CXCL9, 10, and 11 also facilitate angiogenesis by inhibiting the expression of Treg. It has been determined that Treg directly blocks tumour-reactive T cells to stimulate tumour growth (Facciabene et al., 2012).
Overall, Tregs should be seen to be successful in enabling tumour immune tolerance and to be a major tumour progression facilitator in cells. Also, Tregs may contribute substantially to specific tumour angiogenesis development. Therefore, Tregs contribute significantly to tumour development by combining immune suppression and angiogenesis, illustrating the essential nature of directly attacking these cells to promote anti-tumor immunity and tumour progression.