Importance of place

Liver metastasis is a major cause of death for patients with colorectal cancer (CRC), 95% of which are proficient in a type of DNA repair known as mismatch repair and resist immune checkpoint blockade (ICB) therapy. Researchers led by Ludwig Harvard’s Rakesh Jain, Ludwig Lausanne’s Mikaël Pittet and Harvard’s Dai Fukumura explored the causes of this resistance in mouse models of CRC liver metastases. They reported in a November paper in the Proceedings of the National Academy of Sciences that while such cancers implanted subcutaneously in mice respond readily to ICB, those implanted in the colon or liver are as resistant to the immunotherapy as tumors seen in patients—demonstrating the importance of using models, in which tumors are implanted in the tissues where they are normally found. The researchers showed that resistance to ICB is associated with a paucity of dendritic cells—which direct and stimulate T cell responses—in CRC liver metastases. Giving the mice a dendritic cell growth factor, Flt3L, boosted the number of dendritic cells and infiltrating T cells in tumors and sensitized the liver metastases to ICB therapy. The findings suggest new strategies for inducing vulnerability to ICB in CRCs.

This article appeared in the February 2022 issue of Ludwig Link. Click here to download a PDF (1 MB).


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