Endocrine Abstracts

Objectives: The mortality in thyroid cancer (TC) is unacceptably high and novel immune based strategies are necessary, especially for cancers that are resistant to existing therapies. Recently, the receptor SIGLEC15 has been proposed as potential novel target in different cancers, but little is known about its exact function and regulation. Given its high expression in tumor associated macrophages and the high density of these cell in thyroid cancer makes this anti-inflammatory receptor an attractive target to study. Novel insights in the regulation and function of SIGLEC15 will allow us to develop tailored therapies incorporating SIGLEC15 as mechanistic target which will subsequently benefit the growing group of TC patients. Finally, general concepts obtained during this study may be applicable to other cancers as well.

Methods: Using different thyroid cancer cell lines we investigated the effect of cancer conditioned media on the phenotype of primary monocytes and macrophages as well as different monocytic cell lines. Additionally, we performed targeted proteomic analyses to pinpoint mediators in the media that influence SIGLEC15 expression on the immune cells. Subsequently we extended these experiments to co-cultures and trans-well experiments using cancer and (innate) immune cells. Finally, we generated different thyroid cancer and monocytic cell lines with stable SIGLEC15 overexpression to mimic the high expression of SIGLEC15 in the tumor microenvironment.

Results: Comparing the different thyroid cancer conditioned media in their ability to influence SIGLEC15 expression on either primary immune cell or innate immune cell lines we identified several interesting hits that will be validated in future experiments. As engagement of SIGLEC15 with its ligand leads to an anti-inflammatory cascade and induction of pro tumoral mediators we expected to measure an increase in anti-inflammatory cytokines. Surprisingly, when challenging the immune cells with LPS after they were differentiated in tumor conditioned medium, we measured higher levels of different pro-inflammatory cytokines such as TNF-a, IL-6 and lower levels of the anti-inflammatory cytokine IL-10. When culturing immune and thyroid cancer in either trans-well or direct co-cultures we obtained comparable results. Interestingly when culturing immune cells with a stable over expression of SIGLEC15 together with different thyroid cancer cells we observed a strong increase of IL-8.

Conclusion: Our results strengthen the hypothesis that SIGLEC15 plays an important role in the development and progression of thyroid cancer. Targeting this receptor in the context of infiltrating immune cells such as (tumor associated) macrophages might lead to a more pro-inflammatory and anti-tumoral phenotype.