2015: KWF grant for Adema, Boltje and Büll: Blocking Sialic Acids to Boost Cancer Immunotherapy

Tumors have evolved mechanisms to create a local tumor microenvironment enriched for soluble mediators, receptors and cell types (stromal cells, immune cells) that support tumor cell proliferation, survival and persistence. The tumor microenvironment also negatively affects cancer therapies and is highly immunosuppressive thereby preventing killing of cancer cells by immune cells. Elimination or reprogramming of the tumor microenvironment appears crucial for developing effective cancer immunotherapies.

Prof. Gosse Adema

To create a tumor supportive environment cancer cells not only express an altered protein repertoire, they also produce aberrantly high levels of sialic acid sugars. High sialic acid levels of tumors correlate with a poor prognosis of cancer patients. Interestingly, sialic acids mediate tumor cell-extracellular matrix interactions, tumor cell protection from immune cell killing as well as expansion of suppressive immune cell subsets and angiogenesis. Importantly, because of their multilevel involvement, targeting the expression of sialic acids, can potentially affect several different processes in the formation of an immunosuppressive tumor microenvironment at the same time. So far, therapeutic strategies to interfere with the excessively high expression of sialic acids by tumor cells have been limited by the lack of tools and are barely exploited in a preclinical setting. Using rationally designed glycomimetics able to block sialic acid expression human and murine cells, the investigators will address the hypothesis that sialic acid blockade is key to reprogram the immunosuppressive tumor microenvironment. Studies aim to investigate the potency of sialic acid blockade to disintegrate the immunosuppressive tumor microenvironment, to detail its mode of action and to determine its ability to synergize with cancer immunotherapy.