A team of scientists has uncovered dozens of novel genes involved in resistance to therapies that harness the immune system to fight cancer. The findings, which appear in the journal Nature, enhance our understanding of why some cancers are resistant to immunotherapy.
“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,” explains the study’s senior author, Nicholas P. Restifo, a senior investigator at the National Cancer Institute. “The big surprise was that we found many news genes that we never suspected could potentially be involved in preventing the immune system from killing cancer cells.”
The investigators, including co-first author, NYU’s Neville Sanjana, developed a novel use of a gene editing technique, a ‘two-cell type’ CRISPR assay system (2CT CRISPR) that specifically examines how genetic mutations in one cell can affect the interaction between two different cell types.
CRISPR technology allows for the editing of genomes by altering DNA sequences and modifying gene function.
“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,” says Sanjana, core faculty member at the New York Genome Center and assistant professor in NYU’s Department of Biology and Neuroscience and Physiology at NYU School of Medicine. “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.”
The study was aimed at linking the loss of the ability to kill tumor cells with the failure of immunotherapy. The researchers reported that this large gene list uncovered by 2CT CRISPR could serve as a “blueprint” to study the emergence of tumor resistance and eventually lead to more effective immunotherapy treatments for patients.
The innovative 2CT CRISPR screen consisted of human T cells, often referred to as ‘the executioners’ because of the key role they play in attacking cancer, as effectors and human melanoma tumor cells as targets. The melanoma cells were modified by CRISPR and then tested for resistance by applying T cells. Researchers were able to identify which loss-of-function mutations in melanoma reduced the effectiveness of the T cells and led to immunotherapy-resistant tumors.
One of the genes without a previously established role in cancer immunotherapy that the investigators identified was APLNR. The product of this gene is a protein called the apelin receptor, and the study demonstrated for the first time its connection to the JAK-STAT pathway, known to be important for immune response.
The Nature study, the researchers observe, demonstrates that loss of APLNR in a mouse cancer model results in poor prognosis and blocks effective treatment through immunotherapy.
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