Table 3 Patterns in tumor-associated immune cells within the thyroid cancer microenvironment

B cells

Antithyroid antibodies (secreted by B cells) are present in 18–40% of patients with PTC, 39% in those with benign thyroid nodules, and 10–14% of general population [138,139,140,141,142].

Mast Cells

PTC have been found to exhibit dense mast cell infiltration in comparison to normal thyroid tissues. This dense infiltration could be attributed to VEGF-A secretion by thyroid tumor cells which help in recruiting mast cells. Tumor recruiting mast cells play a role in tumor immune escape as these cells contribute to dedifferentiation, invasion, and angiogenesis of thyroid tumor through production of chemokines (CXCL1, CXCL10), histamine, and interleukin 8 [143,144,145].

T cells

Another proposed mechanism for tumor immune escape includes the overexpression of inhibitory checkpoint molecules in tumor associated T cells (Fig. 3). These molecules include PD-1, TIM-3, Lag-3, and TIGIT. The downstream inhibitory signaling of these molecules on T cells has been reviewed before [146] (Fig. 4). These molecules contribute to T cell dysfunction by affecting their production of the inflammatory cytokines IL-2, TNFα, and IFNγ. PD-1 molecule expression was associated with all classes of thyroid cancer with highest prevalence in anaplastic types. Regulatory T cells (Tregs) are a subpopulation of T cells known for their immune suppressive effects and tumor enhancing properties. Tregs exert these pro-tumor actions by expressing PD-1 and CTLA-4, another immune checkpoint modulator. Tregs were found in large amounts in advanced, locally-invasive DTC, lymph node metastases, and ATC. These findings support their role in tumor aggressiveness, and how targeting immune inhibitory Tregs can mediate better thyroid tumor control [74, 147,148,149].

Natural Killer cells (NK)

Patients with aggressive ATC or advanced and metastatic thyroid cancers were reported to have low peripheral blood NK cells in comparison to patients with benign lesions or other control patients. Introduction of IL-12 (an NK activating cytokine) in a murine model of BRAF-mutated thyroid cancer was helpful in restoring the tumor immune elimination properties. –Also, it is to be noted that NK cells could lyse anaplastic thyroid cells ex-vivo. It is hoped that these anti-tumoral activities of NK cells could be used in thyroid cancer immunotherapy [150,151,152,153,154,155,156].

Tumor associated macrophages (TAM)

These cells belong to the monocyte-macrophage lineage. There are two phenotypes of TAMs: M1 expressing IL-1, IL-12, and TNF-α, contributing to immune control over tumors; and M2 expressing IL-10 and CD163, promoting tumor progression and inhibition of tumor immune elimination. It was concluded that in PTC and poorly differentiated thyroid cancer, the density and presence of M2 TAMs correlated with tumor invasion and decreased survival. In anaplastic tumors, the TAMs form greater than 50% of tumor mass [157,158,159].

Dendritic cells

Immature dendritic cells expressing CD1a or S100 were found in PTC human tissue samples, and these cells failed to maintain an immune response to thyroid cancer cells [160,161,162]. A relation between TAMs and inability of dendritic cells to mature and present tumoral antigens has been proposed [163]. Such relation suggests that targeting inhibitory TAMs could enhance dendritic cells differentiation. However, this concept remains yet to be validated in more pre-clinical studies as well as clinical trials.