Stemness and Immunological Features of Thyroid Cancer Cells

Cancer stem cells (CSCs) can initiate and maintain tumours and may drive metastasis, recurrence and resistance to anti-neoplastic therapies. Recent evidence suggests that CSCs possess immunomodulatory capabilities that may enable them to evade host anti-cancer immunity to promote tumorigenicity. CSC immunological functions include evasion from immune clearance, induction of clonal anergy or deletion, and activation of regulatory immune cells. We recently identified Interleukin-8 as a crucial factor that sustains the stemness features of thyroid cancer (TC) cells through the induction, among the others, of OCT4 and SOX2 transcription factors. We generated OCT4/SOX2 overexpressing TC cells and analysed their stemness and immunomodulatory properties. We confirmed that TC cell lines overexpressing OCT4/SOX2 showed, compared to control cells, an increase in stemness features. Accordingly, OCT4/SOX2 TC cells displayed increased tumour incidence and growth when injected at limiting number in mice compared to parental cells. Negative regulators of the immune system, including Programmed cell Death-Ligands 1 and 2 (PD-L1/PD-L2) and the enzyme Indoleamine 2,3-dioxygenase (IDO) are often “hijacked” by tumours to restrain the ability of the immune system to mount an effective anti-tumor response. Here, we show that OCT4/SOX2 expressing TC cells display increased PD1, PD-L1/2 and IDO expression both at mRNA and protein levels with respect to parental cells. Consistently, TC cells overexpressing OCT4 and SOX2, when co-cultured with lymphoid cells, caused a reduction of lymphocyte vitality compared to control cells. Thus, OCT4 and SOX2 are not only key regulators of stemness features but also of immunomodulatory properties of TC cells.