Exploring Macrophage heterogeneity in aggressive cancers.

Anaplastic thyroid cancer (ATC) is a very aggressive and ultrarare undifferentiated thyroid cancer with one of the poorest prognoses in oncology. Macrophages can constitute up to 70% of ATC tumor microenvironment, which may account for therapeutic resistance and aggressiveness. These findings underscore the potential critical role of myeloid cells in this disease. Our study investigates the spatial architecture of ATC tumors and the contribution of myeloid cells in the aggressive behavior of anaplastic tumor cells. Compared to differentiated thyroid cancer characterized by a very low number of macrophages, we confirm that ATC tumors are highly enriched in tumor-associated macrophages. In fact, our analysis revealed distinct “niches” (areas of the tumor that share some common features) associated with specific macrophage subsets, providing new insights into the spatial organization and potential functional roles of myeloid cells in anaplastic tumors.  

These niches can be described according to pathology subtypes. Squamoid ATC niches, defined by squamous tumor cells, are highly infiltrated and enriched in CD206+ macrophages, interacting with tumor cells undergoing epithelial-to-mesenchymal transition. Fusiform ATC niches -defined by spindle-shaped tumor cells- are, on the contrary, highly infiltrated and enriched in CD163+ macrophages, interacting closely with exhausted CD8+ T cells and invasive tumor cells. This is a first step toward a better understanding of the immune spatial architecture of ATC tumors and how macrophages of each niche are contributing to tumor aggressiveness, either through immuno-suppression, promotion of invasion or resistance to treatment. We have for goal to extend this study to other aggressive tumor’ types as PDAC and NSCLC.