A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma. (https://pubmed.ncbi.nlm.nih.gov/38181739/)

These scientists wanted to understand why some people with melanoma, a type of skin cancer, do not respond to a treatment called immune checkpoint blockade (ICB). To do this, they looked at the different cells and genes in the melanoma tumors of people who had not yet received any treatment. They found that the tumor environment helps create a complex pattern of genes in the melanoma cells. They also discovered that a specific group of cells, called mesenchymal-like (MES) cells, which are known to resist targeted therapy, were more common in people who did not respond to ICB.

The scientists found that a protein called TCF4 is very important in controlling the genes in these MES cells. TCF4 helps the cells resist the immune system and targeted therapy. However, when the scientists blocked TCF4 with a special drug, the MES cells became more sensitive to the treatment and the immune system. This means that by targeting TCF4, the scientists were able to make the cancer cells easier to kill with the treatment.

In summary, these scientists discovered that certain cells in melanoma tumors can resist immune checkpoint blockade treatment. They also found that a protein called TCF4 helps these cells resist the treatment, but by blocking TCF4, the cells become easier to kill with the treatment. This is an important step in understanding how to make treatments more effective for people with melanoma.

Pozniak J., Pedri D., Landeloos E., Van Herck Y., Antoranz A., Vanwynsberghe L., Nowosad A., Roda N., Makhzami S., Bervoets G., Maciel LF., Pulido-Vicuna CA., Pollaris L., Seurinck R., Zhao F., Flem-Karlsen K., Damsky W., Chen L., Karagianni D., Cinque S., Kint S., Vandereyken K., Rombaut B., Voet T., Vernaillen F., Annaert W., Lambrechts D., Boecxstaens V., Saeys Y., van den Oord J., Bosisio F., Karras P., Shain AH., Bosenberg M., Leucci E., Paschen A., Rambow F., Bechter O., Marine JC. A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma. Cell. 2024 Jan 4;187(1):166-183.e25. doi: 10.1016/j.cell.2023.11.037.