Chemokines, signaling proteins that mediate the traffic of immune cells, help T-cells home in on tumors and can affect tumor immunity and the outcome of immunotherapy. In a June paper in Cancer Cell, Ludwig Lausanne Director George Coukos and his colleagues showed that two key chemokines, CCL5 and CXCL9, are consistently implicated in T cell infiltration into solid tumors. CCL5 is expressed by cancer cells, while CXCL9 is produced by macrophages and dendritic cells, immune cells that are usually present in solid tumors. George and his team report that when T cells drawn by CCL5 reach the tumor and are activated, they release a signaling protein called interferon-γ. This causes macrophages and dendritic cells in the tumor to secrete CXCL9, which dramatically boosts the infiltration of circulating T cells. The researchers show that when cancer cells suppress production of CCL5, CXCL9 expression drops, resulting in the progressive depletion of killer T cells in tumors. This loss of CCL5 expression correlates with a chemical modification to DNA known as epigenetic silencing that suppresses the expression of targeted genes. CCL5 and CXCL9 could be useful biomarkers for immunotherapy and help identify patients more likely to be responsive to immunotherapies. The findings will also inform new strategies for cancer immunotherapy.
This article appeared in the November 2019 issue of Ludwig Link. Click here to download a PDF (1 MB).