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CRISPR study finds new genes that create T-cell resistant cancer

Large-scale gene editing study gives new insights into why immunotherapy fails in the majority of cancer patients.

By Amy Wallace
CRISPR study finds new genes that create T-cell resistant cancer
Dr. Neville Sanjana, core faculty member at the New York Genome Center, assistant professor of biology, New York University, and assistant professor of neuroscience and physiology at NYU School of Medicine, with a Sanjana Lab team member. Photo courtesy the New York Genome Center

Aug. 7 (UPI) -- Researchers have used 2CT CRISPR gene-editing technology to identify dozens of new genes that are responsible for T-cell resistant cancer.

A team of researchers at the New York Genome Center, New York University, the Broad Institute and the National Cancer Institute collaborated on the CRISPR cancer study, which was published today in Nature.

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They developed a new use for the 2CT CRISPR, or two-cell type CRISPR, that analyzes how genetic mutations in one cell can affect the interaction between two different cell types.

"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," Dr. Nicholas P. Restifo, a senior investigator at the National Cancer Institute, said in a press release. "The big surprise was that we found many new genes that we never suspected could potentially be involved in preventing the immune system from killing cancer cells."

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The large gene list uncovered by 2CT CRISPR could provide a blueprint to study the emergence of tumor resistance and lead to more effective immunotherapy treatments.

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Researchers conducted the 2CT CRISPR screen on human T-cells and human melanoma tumor cells as their targets. The melanoma cells were modified by CRISPR and tested for resistance by applying T-cells and resulting in 19,000 genes in tumor cell's genome being knocked out.

"We were very encouraged by the hits from the 2CT CRISPR screen in pinpointing which genes are involved in immunotherapy resistance, as well as revealing so many novel genes. For example, 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. Seeing these genes at the top of the list is a really nice sign that the genetic screen yielded meaningful data," Dr. Neville Sanjana, Core Faculty Member at the New York Genome Center, Assistant Professor of Biology, New York University, and Assistant Professor of Neuroscience and Physiology at NYU School of Medicine said.

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"It has been really wonderful to collaborate with the Restifo Lab. This kind of project is only possible with a team with diverse expertise in gene editing, functional genomics and cancer immunotherapy."

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