Genes that play a role in cancer's evasion of the immune system have been identified.
Immunotherapy can be a very effective treatment against cancer, but cancer cells can become resistant to treatment by learning to avoid the immune system. The underlying genetics that allow this to happen remain poorly understood. Now, scientists at the University of Toronto, Canada, alongside collaborators from Agios Pharmaceutical in Cambridge, Massachusetts, have identified genes that play an important role in enabling cancer cells to avoid being destroyed by killer T-cells – an important component of the immune system.
'It's very important to understand at the molecular level how cancer develops resistance to immunotherapies in order to make them more broadly available', said Professor Jason Moffat, who led the study.
The research, published in Nature, used the CRISPR genome editing to delete individual genes from six genetically diverse mouse cancer cell lines. The researchers then grew the cancer cells in vitro with killer T-cells and observed whether the deletion made the cancer cells more or less sensitive to destruction by the killer T-cells.
In this way they identified 182 core genes across the different cancer cell lines that increased either the sensitivity or the resistance of cancer cells to the killer T-cells. Some of the genes identified were already known to be mutated in patients that are resistant to immunotherapy, but many had no known link to immune system evasion.
Genes that are involved in autophagy – a kind of self-digesting recycling process of cells – were also identified as key players in cancer cell's immune evasion. The scientists thus believed that targeting autophagy genes could enhance cancer immunotherapy treatment. However, the team found that deleting certain autophagy genes in pairs resulted in the cancer cells not being destroyed by killer T-cells. This is important as patients with tumours that already have a mutation in one autophagy gene, who are given a treatment that combines immunotherapy with a drug targeting another autophagy gene could make the disease worse in that patient.
'We found this complete inversion of gene dependency,' said Professor Moffat. 'We did not anticipate this at all. What it shows us is that genetic context – what mutations are present – very much dictates whether the introduction of the second mutation will cause no effect, resistance or sensitivity to therapy.'
The researchers hope that their findings will lay the groundwork to explore the effects different combinations of mutations have across different types of cancer and subsequently be the first steps towards the development of new immunotherapies that could benefit larger groups of patients.
'It's important to not just find genes that can regulate immune evasion in one model of cancer, but what you really want is to find those genes that you can manipulate in cancer cells across many models, because those are going to make the best therapeutic targets,' said Keith Lawson, PhD student and co-lead author of the study.