November 20, 2017Oncology
According to a study published online in Nature (7 August 2017), genes have been identified that are necessary in cancer cells for immunotherapy to work. These results address the problem of why some tumors don't respond to immunotherapy or respond initially but then stop as tumor cells develop resistance to immunotherapy.
Cancer immunotherapy relies on T cells, a type of cell in the immune system, to destroy tumors. The authors have previously shown that the infusion of large numbers of T cells can trigger complete regression of cancer in patients, and that T cells can directly recognize and kill tumor cells. However, some tumor cells are resistant to the destruction unleashed by T cells.
To investigate the basis for this resistance, the authors sought to identify the genes in cancer cells that are necessary for them to be killed by T cells. Working with a melanoma tumor cell line, the authors 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, the authors identified more than 100 genes that may play a role in facilitating tumor destruction by T cells. Once the authors 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. Results showed 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.
According to the authors, the results show that many more genes than were originally expected play a vital role in dictating the success of cancer immunotherapies. The authors also noted that this gene list could serve as a blueprint to study the emergence of tumor resistance to T cell-based cancer therapies, and that if this set of genes is validated in clinical trials, then this data could eventually lead to more effective treatments for patients.