Secreted Factors by Anaplastic Thyroid Cancer Cells Induce Tumor-Promoting M2-like Macrophage Polarization through a TIM3-Dependent Mechanism

SIMPLE SUMMARY: Among the different types of thyroid cancer, anaplastic thyroid cancer (ATC) is one of the most aggressive tumors. Characterized for its undifferentiated cells, it spreads quickly to distant organs and does not respond well to standardized therapy. Therefore, there is a critical need to identify new targets that can be translated into therapeutic approaches. ATCs are heavily infiltrated by Tumor-Associated Macrophages (TAMs), and its infiltration density is associated with decreased survival. However, the functional role of TAMs in ATC is still unclear. Our results provide valuable insights into the processes in which soluble factors produced by ATC cells induce M2-like polarization of human monocytes through T cell immunoglobulin and mucin-domain containing protein-3 (TIM3). TIM3 in TAMs should now be further evaluated as a possible potential novel target for treating ATC. ABSTRACT: Anaplastic thyroid cancer (ATC) is a highly aggressive type of thyroid cancer (TC). Currently, no effective target treatments are available that can improve overall survival, with ATC representing a major clinical challenge because of its remarkable lethality. Tumor-associated macrophages (TAMs) are the most evident cells in ATCs, and their high density is correlated with a poor prognosis. However, the mechanisms of how TAMs promote ATC progression remain poorly characterized. Here, we demonstrated that the treatment of human monocytes (THP-1 cells) with ATC cell-derived conditioned media (CM) promoted macrophage polarization, showing high levels of M2 markers. Furthermore, we found that STAT3 was activated, and this was correlated with an increased expression and secretion of the inflammatory cytokine interleukin-6. Remarkably, the M2-like macrophages obtained revealed tumor-promoting activity. A cytokine array analysis demonstrated that M2-like macrophage-derived CM contained high levels of TIM3, which is an important immune regulatory molecule. Consistently, TIM3 expression was up-regulated in THP-1 cells cultured with ATC cell-derived CM. Moreover, TIM3 blockade significantly reversed the polarization of THP-1 cells induced by ATC cell-secreted soluble factors. We validated the clinical significance of the TIM3 in human TC by analyzing public datasets and found that the expression of TIM3 and its ligand galectin 9 was significantly higher in human TC tissue samples than in normal thyroid tissues. Taken together, our findings identified a new mechanism by which TIM3 induces tumor-promoting M2-like macrophage polarization in TC. Furthermore, TIM3 interference might be a potential tool for treatment of patients with ATC.