CRISPR identifies essential genes for cancer immunotherapy

Researchers have used CRISPR to stop the expression of individual genes in cancer cells, by knocking out every known protein-encoding gene in the human genome and then testing the ability of the gene-modified melanoma cells to respond to T cells, they found more than 100 genes that may play a role in facilitating tumour destruction by T cells.

“There is a great deal of interest in cancer immunotherapy, especially for patients who have metastatic cancer,” said Dr Nicholas Restifo, a senior investigator with National Cancer Institute’s (NCI’s)Centre for Cancer Research, “The response to immunotherapy can be fantastic, but understanding why some patients don’t respond will help us improve treatments for more patients.”

Cancer immunotherapy relies on T cells, a type of cell in the immune system, to destroy tumours. Dr Restifo and his colleagues have previously shown that the infusion of large numbers of T cells can trigger complete regression of cancer in patients. They and others have also shown that T cells can directly recognise and kill tumour cells.

However, some tumour cells are resistant to the destruction unleashed by T cells. To investigate the basis for this resistance, the researchers sought to identify the genes in cancer cells that are necessary for them to be killed by T cells. They identified genes that are necessary in cancer cells for immunotherapy to work, addressing the problem of why some tumours don’t respond to immunotherapy or respond initially but then stop as tumour cells develop resistance to immunotherapy.

Once the team identified these “candidate” genes, they sought additional evidence that these genes play a role in susceptibility to T cell-mediated killing. To this end, they examined data on “cytolytic activity,” or a genetic profile that shows cancer cells are responding to T cells, in more than 11,000 patient tumours from The Cancer Genome Atlas, a collaboration between NCI and the National Human Genome Research Institute, also part of NIH. They found that many the genes identified in the CRISPR screen as being necessary for tumour cells to respond to T cells were indeed associated with a tumour cytolytic activity in patient samples.

One such gene is called APLNR. The product of this gene is a protein called the apelin receptor. Although it had been suspected to contribute to the development of some cancers, this was the first indication of a role in the response to T cells. Further investigation of tumours from patients resistant to immunotherapies showed that the apelin receptor protein was non-functional in some of them, indicating that the loss of this protein may limit the response to immunotherapy treatment.

Dr Shashank Patel, the first author of the study, said the results show that “Many more genes than we originally expected to play a vital role in dictating the success of cancer immunotherapies.”

The researchers wrote that this gene list could serve as a blueprint to study the emergence of tumour resistance to T cell-based cancer therapies. Dr Restifo noted that if this set of genes is validated in clinical trials, then this data could eventually lead to more effective treatments for patients.

“If we can truly understand mechanisms of resistance to immunotherapy, we might be able to develop new therapeutics,” he said. “In fact, in the future, this knowledge could speed the development of a new category of drugs that can circumvent these escape mechanisms of tumour cells and help patients experience complete responses.”