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 tumors from The Cancer Genome Atlas, a collaboration between NCI and the National Human Genome Research Institute, also part of NIH. They found that a number of the genes identified in the CRISPR screen as being necessary for tumor cells to respond to T cells were indeed associated with tumor 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 tumors from patients resistant to immunotherapies showed that the apelin receptor protein was nonfunctional in some of them, indicating that the loss of this protein may limit the response to immunotherapy treatment.
Shashank Patel, Ph.D., the first author of the study, said the results show that “many more genes than we originally expected 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 tumor 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 tumor cells and help patients experience complete responses.”