Immunotherapy is a mode of treatment which uses a patient's own immune system to destroy cancer cells. IT can be highly effective for some patients, but not all.
'This is the first step for systematically identifying the reasons immunotherapy is not working for many cancer patients,' said senior author Dr Nicholas Restifo at the National Cancer Institute in Bethesda, Maryland. 'The hope is to help scientists and clinicians find a way around the obstacles so that more patients can benefit from this promising treatment modality.'
Researchers created a novel 'two-cell type' CRISPR assay consisting of human melanoma cells and T-cells, to investigate how these cells interact. They used CRISPR/Cas9 to knock out single genes in the human melanoma cells in order to identify which ones create resistance to T-cells.
'We cast a wide, deep net and conducted an unbiased survey of all of the 19,000 genes in the cancer's genome - not just the genes that are known to be involved in creating immunotherapy-resistant tumours,' said Dr Restifo. 'The big surprise was that we found many new genes that we never suspected could potentially be involved in preventing the immune system from killing cancer cells.'
The 100 most necessary genes were found to affect the presence of proteins specifically found on the surface of cancer cells, known as neoantigens. These are usually recognised by T-cells and trigger the release of cytokines, proteins which modulate the body's immune response.
Next, the researchers assessed 36 different cancer types for expression of these genes, searching genetic data from nearly 11,500 tumours from the Cancer Genome Atlas database. They identified a core set of 19 genes associated with cytokine activity across different cancer types. The researchers also found mutations in these genes were more common in patients who did not respond to the drug ipilimumab, a type of immunotherapy.
In particular, the researchers identified multiple mutations in the APLNR gene, which had previously not been linked to the effectiveness of cancer immunotherapy. When they mutated APLNR in mice, it reduced the efficacy of immunotherapy.
Dr Restifo told Genetic Engineering and Biotechnology News that he hoped the findings could act as a 'blueprint' for further research into cancer therapies that hinge on T-cell attack. 'Looking at mutations in these genes in individual patients who failed immunotherapy may enable physicians to devise the most appropriate treatments for each individual patient, according to their essential gene profiles,' he said.