Scientists from the Dana-Farber Cancer Institute in Boston, USA, have discovered a genetic mechanism in kidney cancer and melanoma cells that explains the mechanism for resistance to immunotherapy drugs called checkpoint inhibitors. This might help to explain why some people respond to immunotherapy, while others do not. The research is published in two articles in the journal Science.

The scientists say the findings may lead to potential new drug targets and the benefits of immunotherapy treatment might be extended to different types of cancer.

The researchers discovered that resistance to immune checkpoint inhibitors is controlled by changes in a group of genes that produce proteins that regulate how DNA is packaged in cells, called ARID2, PBRM1, and BRD7.

Clear cell renal cell carcinoma (ccRCC) patients who benefited from treatment with nivolumab or similar drugs had tumours which lacked a functioning PRBM1 gene. Loss of the PBRM1 gene function caused the cancer cells to have increased expression of other genes, which stimulate the immune system.

Similarly, when the PBRM1 gene in melanoma cells was inactivated, the melanoma cells became more sensitive to interferon-gamma produced by T cells, and in response produced signalling molecules that recruited more tumour-fighting T cells into the tumour.

The researchers also suggest that the two other genes – ARID2 and BRD7 – are also found mutated in some cancers, and those cancers may also respond better to checkpoint inhibitors.

The protein products of these genes, the authors note, “represent targets for immunotherapy, because inactivating mutations sensitise tumour cells to T-cell mediated attack.” Finding ways to alter those target molecules, they add, “will be important to extend the benefit of immunotherapy to larger patient populations, including cancers that thus far are refractory to immunotherapy.”

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