by Jonathan Bailey
A new study has identified genes that are necessary in cancer cells for immunotherapy to work, addressing the problem of why some tumors don’t respond to immunotherapy or respond initially but then stop as tumor cells develop resistance to immunotherapy.
The study, from the National Cancer Institute (NCI), was led by Nicholas Restifo, M.D., and published in Nature, Aug. 7, 2017.
“There is a great deal of interest in cancer immunotherapy, especially for patients who have metastatic cancer,” said Dr. Restifo. “The response to immunotherapy can be fantastic, but understanding why some patients don’t respond will help us improve treatments.”
Cancer immunotherapy relies on T cells, a type of cell in the immune system, to destroy tumors. 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 recognize and kill tumor cells. However, some tumor cells are resistant to the destruction unleashed by T cells.
Working with a melanoma tumor cell line, the researchers used a gene editing technology called CRISPR that “knocks out,” or stops 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 tumor destruction.
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. They found that a number of the genes identified in the CRISPR screen as being necessary for tumor cells to respond to T cells. 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.
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.”
Dr. Restifo noted that if this set of genes is validated in clinical trials, then the 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.”