Gene editing tool reveals why some patients with cancer fail to respond to immunotherapy.
Scientists have identified genes that are essential to the efficacy of cancer immunotherapy, according to a study published in Nature.
Immunotherapy relies on T cells to attack and destroy tumors. Although this approach continues to show promise in the oncology space, some patients are unresponsive or develop treatment resistance. Improving immunotherapy continues to draw interest among scientists.
“There is a great deal of interest in cancer immunotherapy, especially for patients who have metastatic cancer,” said senior author Nicholas Restifo, MD. “The response to immunotherapy can be fantastic, but understanding why some patients don’t respond will help us improve treatments for more patients.”
The investigators sought to investigate treatment-resistance by identifying the genes in cancer cells necessary for them to be killed by T cells in a melanoma tumor cell line.
They used the gene editing tool CRISPR to knock out the expression of individual genes in cancer cells, and tested the ability of gene-modified melanoma cells to respond to T cells. As a result, more than 100 genes that may play a role in driving T cell tumor destruction were identified.
To further confirm the roles of candidate genes in susceptibility to T cell attacks, the investigators examined cytolytic activity data in more than 11,000 patient tumors from The Cancer Genome Atlas.
Several of the essential genes identified via CRISPR were confirmed to be associated with tumor cytolytic activity in patient samples, particularly the gene APLNR.
It has been suspected that APLNR contributes to the development of some cancers, but this was the first time it has been indicated for its role in the response to T cells.
Further investigation of immunotherapy-resistant tumors showed the apelin receptor protein was nonfunctional in some, suggesting the loss of this protein may limit the response to immunotherapy.
“Many more genes than we originally expected play a vital role in dictating the success of cancer immunotherapies,” said first author Shashank Patel, PhD.
The gene list could serve as a blueprint for future studies on treatment resistance to T cell-based cancer therapies, the authors noted. If validated, the data could potentially lead to more effective treatment options.
“If we can truly understand mechanisms of resistance to immunotherapy, we might be able to develop new therapeutics,” Dr Restifo concluded. “In fact, in the future, this knowledge could speed the development of a new category of drugs that can circumvent these escape mechanisms of tumors cells and help patients experience complete responses.”