How to overcome the resistance to anti-PD1/anti-CTLA4 therapy

Checkpoint inhibitors (anti-PD1, anti-PDL1, and anti-CTLA4) are revolutionizing treatment options and expectations for patients with melanoma. However, only a subset of patients responds to these treatments. In the latest issue of Nature[1], researchers from the University of Chicago show how tumors shield themselves from T cells by producing high levels of β-catenin.

Researchers analyzed tumor tissue samples from nearly 197 patients with melanoma. They compared 91 patients who did not have T cell invasion to 106 patients who have T cell invasion. Results showed that 49% of the tumors that blocked T cell infiltration had high levels of beta-catenin.

They also discovered that tumor cells without β-catenin produce CCL4, which attracts CD103+ dendritic cells. But CCL4 expression is suppressed by high levels of β-catenin. Active β-catenin signaling within tumor cells suppresses the recruitment of CD103+ dendritic cells.

Next, they tested two checkpoint inhibitors in the mice with melanoma. They found that tumors that lacked beta-catenin responded to treatment. Tumors with beta-catenin did not. Injection of CD103+ dendritic cells (Flt3-L BM-DC, Flt3 ligand-induced bone-marrow dendritic cells) directly into the tumor could overcome the resistance to anti-PD1/anti-CTLA4 therapy.

Flt3-L BM-DC

[1] Nature. 2015, doi:10.1038/nature14404.


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