Th17/Treg cell balance in patients with papillary thyroid carcinoma: a new potential biomarker and therapeutic target

Abstract

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid carcinoma. The most effective treatment for PTC is surgical resection, and patients who undergo surgery have good survival outcomes, but some patients have distant metastasis or even multiorgan metastases at the time of initial diagnosis. Distant metastasis is associated with poorer prognosis and a higher mortality rate. Helper T lymphocyte 17 (Th17) cells and regulatory T lymphocytes (Tregs) play different roles in PTC, and the Th17/Treg balance is closely related to the progression of PTC. Th17 cells play anticancer roles, whereas Tregs play cancer-promoting roles. A Th17/Treg imbalance promotes tumor progression and accelerates invasive behaviors such as tumor metastasis. Th17/Treg homeostasis can be regulated by the TGF-β/IL-2 and IL-6 cytokine axes. Immune checkpoint inhibitors contribute to Treg/Th17 cell homeostasis. For PTC, monoclonal antibodies against CTLA-4, PD-1 and PD-L1 inhibit the activation of Tregs, reversing the Th17/Treg cell imbalance and providing a new option for the prevention and treatment of PTC. This article reviews the role of Tregs and Th17 cells in PTC and their potential targets, aiming to provide better treatment options for PTC.

Keywords: Th17; Th17/Treg homeostasis; Treg; checkpoint blockade; papillary thyroid carcinoma (PTC).

Figure 1

Th17/Treg cell differentiation. Th17/Treg cells differentiate from CD4⁺ T cells. The presence of IL-2 and TGF-β stimulates the initial development of CD4⁺ T cells into Tregs, which express transcription factors such as STAT5 and FoxP3 and secrete cytokines, including TGF-β, IL-10, and IL-35. Tregs play an immunosuppressive/tolerance-promoting role by inhibiting the activation and proliferation of a variety of immune cells, such as NK cells and CD8⁺ T cells. TGF-β, IL-6, and IL-21 promote the development and stabilization of Th17 cells. Th17 cells are most commonly classified by their expression of RORγt and STAT3. Th17 cells can release proinflammatory cytokines to mediate inflammation, inhibit tumor growth, and promote cancer cell apoptosis.

Figure 2

Functional plasticity of Tregs and Th17 cells. Multiple molecules can affect the functional plasticity of Tregs and Th17 cells. TGF-β and IL-2 induce the differentiation of Tregs, which exert immunosuppressive functions and promote immune escape through the secretion of inhibitory cytokines such as IL-10 and VEGF or through the cell-mediated engagement of inhibitory checkpoint molecules such as GITR, PD-1, CTLA-4, TIGIT, CD25, IDO1, and GARP. IL-1β induces alternative splicing of FoxP3, inhibits Treg cell differentiation, and promotes IL-17 production. RORγt is a key transcription factor in Th17 cell development. The SKI-SMAD4 complex inhibits RORγt, in which the SKI protein inhibits acetylation of the Rorc site. TGF-β was shown to modulate the SKI-SMAD4 complex, and in the presence of TGF-β, SKI is degraded, allowing RORγt to be expressed in CD4⁺ T cells and ultimately driving Th17 cell differentiation. IL-2 induces STAT5, reduces STAT3 binding, and inhibits Th17 differentiation. PTEN in Th17 cells inhibits the IL-2 signaling pathway, reduces STAT5 and Treg differentiation, and upregulates STAT3. When FoxP3⁺ Tregs are exposed to IL-6 with or without IL-1β and IL-23, FoxP3 is downregulated, which promotes the expression of Th17 genes, including IL-17, IL-22, IL-23R, and RORγt. TGF-β and PGE2 can also induce Th17-to-Treg cell conversion.

Figure 3

Tregs and PTC. Tregs exert immunosuppressive functions by producing inhibitory cytokines such as IL-10, CXCL8, and VEGF and promote tumor angiogenesis. The inhibitory receptors IDOI and PD-1 on the surface of Tregs can inhibit the activity of NK cells and CD8⁺ T cells, promoting immune escape. PD-I can also bind to PD-L1 on the surface of PTCs to promote the proliferation of tumor cells. CD28 and CTLA-4 can competitively bind to CD80/CD86 on the surface of APCs, thereby enhancing the inhibitory function of Tregs. FoxP3 can maintain the inhibitory effect of Tregs on the immune system by forming a 400–800 kDa multiprotein complex with its transcription partners. Thyroid cancer cells can produce VEGF, recruit mast cells to infiltrate thyroid cancer tissue, and stimulate mast cells to produce IL-6, TNF-α, GM-CSF and CXCL-10, accelerating tumor growth. Thyroid cancer cells can also release CCL20 and CXCL8, which promote PTC invasion and metastasis in vitro. The miR-125b gene negatively regulates the expression of FoxP3 and promotes autophagy in thyroid cancer. IFN-α/β can increase the expression of PDE4 in Tregs, suppress the production of cAMP, and promote the apoptosis of thyroid tumor cells. NKG2D on the surface of NK cells can bind to UL-16 on the surface of thyroid cancer cells and cause the apoptosis of tumor cells.

Figure 4

Th17 cells and PTC. Th17 cells exert indirect antitumor effects by secreting chemokines such as CXCL-9 and CXCL-10 to attract effector cells such as Th1 and CD8⁺ T cells and NK cells to accumulate and kill tumor cells in tumor tissues. Th17 cells can also inhibit the formation of tumor blood vessels and promote PTC cell apoptosis by producing IFN-γ, TNF-α and IL-17. IL-17 can enhance the effect of IL-6, transforming CD4⁺ T cells into Th17 cells. PTC cells can produce CCL2, which stimulates monocytes to produce IL-17, promoting tumor cell proliferation.

Figure 5

Checkpoint blockades reverse the Th17/Treg imbalance and improve the treatment of PTC.