Some 40% of melanoma patients fail to benefit from even a combination of anti-PD1 and anti-CTLA4 checkpoint blockade. This is often because their “cold” tumors are insufficiently infiltrated by tumor targeting T cells. Ludwig Lausanne’s Ping-Chih Ho and colleagues reported in a February paper in Nature Immunology a cellular mechanism that heats up “cold” melanoma tumors and an existing drug that can induce that effect in a mouse model of the cancer. Ping-Chih and his team compared hot and cold melanoma tumors and identified a metabolic protein, UCP2, that is highly expressed in the former. They then engrafted melanoma tumors that could be prompted to express high levels of UCP2 into mice and showed that UCP2 expression drew killer T cells and conventional type 1 dendritic cells (cDC1), which activate killer T cells, into the tumors. Mice engineered to lack cDC1 cells did not show this response. In cold melanoma tumors, inducing UCP2 expression before treatment with an anti-PD1 antibody elicited robust anti-tumor immune responses that significantly extended survival of mice. The researchers showed that a diabetes drug known to induce UCP2 expression, rosiglitazone, could also sensitize cold tumors to checkpoint blockade and extend the survival of mice. Notably, the drug induced UCP2 expression in cultures of melanoma cells obtained from patients as well.
This article appeared in the July 2019 issue of Ludwig Link. Click here to download a PDF (8 MB).