Cancer can't hide from the immune system anymore - scientists are on the verge of identifying every single gene mutation that enables tumors to resist the anti-cancer immune cell attack.
Using a new application of the lauded CRISPR-CAS9 gene editing system, a team of scientists from the New York Genome Center, New York University, the Broad Institute, and the National Cancer Institute conducted a scan of the entire genome of the human melanoma tumor. The new gene editing technique is called two-cell type CRISPR assay system (2CT CRISPR).
“We cast a wide, deep net and conducted an unbiased survey of all of the 19,000 genes in the cancer's genome - not just the genes that are known to be involved in creating immunotherapy-resistant tumors," explained senior author Dr. Nicholas P. Restifo from the National Cancer Institute.
2CT-CRISPR is designed to flesh out the details of how the genetic alterations found in one cell impact how two different cell types communicate, using human T cells and human melanoma tumor cells. T cells are often the main ingredient in immunotherapy drugs because of their natural affinity for targeting cancerous cells. For this particular study, Restifo and the other researchers wanted to know: How are tumors avoiding the power of immunotherapy?
The new system allowed the each of the 19,000 tumor genes to be knocked out and tested for resistance - one at a time. This way, researchers could clearly associate a particular gene mutation with increased tumor resistance. At the end of the scan, the system identified many genes involved in helping tumors resist immunotherapy, including genes that scientists hadn’t realized were involved in tumor defense at all.
The study scientists then compared their findings to genes from the Cancer Genome Atlas, which contains genes spanning thousands of tumor and cancer types. In addition to finding gene mutations specific to melanoma’s resistance to immunotherapy, the comparison strengthened the idea that there is a “core set” of genes that are required for the immune system to successfully target any type of cancer.
“The top two hits - HLA and B2M - form a complex that is required for antigen presentation and thus required for the T cells to see and attack the cancer,” explained co-first author Dr. Neville anjana from the New York Genome Center. “Seeing these genes at the top of the list is a really nice sign that the genetic screen yielded meaningful data.”
Future studies building on the current findings could include other types of immune cells, using 2CT-CRISPR to see how different cell types work in different environments of gene mutations.
"This is the first step for systematically identifying the reasons immunotherapy is not working for many cancer patients," Restifo said. "The hope is to help scientists and clinicians find a way around the obstacles so that more patients can benefit from this promising treatment modality."
The present study was published in the journal Nature.
Source: New York Genome Center
