Table 1.

Immune cells in thyroid cancer microenvironment.

Immune Cells	Reported Data	References
Tumor-associated macrophages	ATCs have the highest density of TAMs in tumor microenvironment, and this correlates with poorer prognosis.	[31]
	In PTCs, the presence of TAMs is lower but a similar correlation exists with clinical outcomes, as more lymph node metastases, larger tumors, and decreased survival.	[31,32,33,34]
	In vitro studies reported that TAMs can promote invasiveness of human TC cell lines through CXCL8/IL-8 secretion.	[34]
	A retrospective study of TCs patients reported a positive association between the number of tumor-infiltrating macrophages and enhanced disease-free survival.	[35]
Dendritic cells	Immature DCs poorly induce T cell and NK cell-mediated responses and they can even inhibit immune responses producing suppressive cytokines, such as IL-10 and TGF-β.	[41]
	Tregs and DCs are elevated in human PTCs.	[43]
Tumor-associated neutrophils	An independent association is found between NLR increase and an incomplete response to therapy in DTC.	[66]
	In human TC samples, neutrophil density correlated with tumor size, suggesting a potential tumor-promoting role of TANs in TC.	[69]
Natural killer cells	ATC cell lines in vitro are responsive to NK cell-mediated lysis. Furthermore, the cells secreted CXCL10/IP-10 when stimulated by IFN-γ and demonstrated an ability to attract CXCR3+ NK cells.	[72,73]
	Other studies reported NK dysfunction in tumor-bearing LSL-BrafV600E/TPO-Cre mice with diminished splenocyte-mediated cytotoxicity, due to NK and CD8+ T cells. The treatment with exogenous IL-12 and anti-TGF-β partially restored, this diminished cytotoxicity.	[75]
T cells	In human PTC, lymphocyte density is associated with improved overall survival and lower recurrences.	[82,83]
	A study showed that proliferating lymphocytes could predict improved disease-free survival in children and young adults.	[84]
	Infiltration of CD8+ T cells into thyroid tumors was associated with improved disease-free survival. CD8+, CD4+ T cells, and B cells were positively correlated with reduced tumor sizes.	[35]
	A study found a higher risk of relapse in the presence of elevated infiltration of CD8+ T cells.	[85]
	Tregs switch off immune responses, favoring disease progression and metastases to lymph nodes in different tumors; their presence in PTCs is associated with a more aggressive disease.	[93,94]
	The percentage of Treg increased in peripheral blood and in the tumor tissues of PTC patients compared to that of MNG patients, and it was associated with aggressiveness.	[95]
	A higher density of double-negative T cells has been reported in TC patients. These T cells seem to reduce the proliferation and cytokine production of neighboring activated effector T cells.	[94,97]
Mast cells	MCs infiltration was reported in 95% of PTC samples whose extent correlated with extrathyroidal extension of tumors, they are also present in PDTC and ATC, and their density correlates with tumor invasiveness.	[113]
	A study revealed a higher presence in the intratumoral and peritumoral areas of follicular variant of PTC in comparison to adenoma.	[114]
	A protumorigenic role of MCs and their mediators in TC has been shown.	[112]
	MCs, by releasing specific mediators as CXCL8/IL-8, improve the acquisition of mesenchymal and stem-like characteristics of TC cells, therefore promoting cancer progression.	[113]

ATCs: Anaplastic thyroid cancers; DCs: Dendritic cells; MCs: Mast cells; NK: Natural Killer; NLR: Neutrophil-to-lymphocyte ratio; PDTC: Poorly differentiated thyroid cancer; PTC: Papillary thyroid cancer; TAMs: Tumor-associated macrophages; TANs: Tumor-associated neutrophils; TC: Thyroid cancer; TME: Tumor microenvironment.