In a new study, researchers from the National Institutes of Health (NIH), Georgetown University School of Medicine, New York University, the New York Genomics Center, the University of Pennsylvania, the Broad Institute, and the Massachusetts Institute of Technology identified cancer. The genes necessary for immunotherapy to work, which solves the problem of why some tumors do not respond to immunotherapy, or react initially, but do not respond as tumor cells become resistant to immunotherapy. The relevant research results were published online in the Nature Journal on August 7, 2017, and the title of the paper is "Identification of essential genes for cancer immunotherapy."
Dr. Nicholas Restifo, senior researcher at the NIH Cancer Research Center, said, “Many people are very interested in cancer immunotherapy, especially for patients with metastatic cancer. It is wonderful to respond to immunotherapy, but understand why Failure to respond to patients will help us improve treatment for more patients."
Cancer immunotherapy relies on T cells to destroy tumors. Dr. Restifo and his colleagues have previously shown that infusion of large numbers of T cells can trigger a complete regression of cancer in patients. They and others have also confirmed that T cells can directly recognize and kill tumor cells. However, some tumor cells are resistant to T cell-initiated attacks. To investigate the basis of this resistance, these researchers sought to identify which genes in cancer cells are necessary for their killing by T cells.
By studying a melanoma cell line, these researchers used a gene editing technique called CRISPR to knock out individual genes in cancer cells. By knocking out every known protein-coding gene in the human genome and subsequently testing the ability of these genetically modified melanoma cells to respond to T cells, they found that more than 100 genes may play a role in promoting T cell destruction of tumors. effect.
Once these researchers identified these "candidate" genes, they sought further evidence to prove that these genes play a role in the sensitivity of cancer cells to T cell-mediated killing. To this end, they studied data on “cytolytic activity†in more than 11,000 patient tumors from The Cancer Genome Atlas, or genetic maps showing how cancer cells respond to T cells. . They found that multiple genes identified in CRISPR screens are required for tumor cells to respond to T cells because they do correlate with tumor cell killing activity in patient tumor samples.
One of the genes is APLNR. This gene encodes a protein called the apelin receptor. Although it has been hypothesized that it promotes some cancer production, this is the first time it has been shown to play a role in the response of cancer to T cells. Further studies of tumors from patients with immunotherapeutic resistance suggest that apelin is not functional in some tumors, suggesting that the lack of this protein may limit the response of tumors to immunotherapy.
Dr. Shashank Patel, the lead author of the paper, said the results suggest that "more genes than we originally expected play a crucial role in indicating whether cancer immunotherapy is successful."
The researchers write that this list of genes may serve as a blueprint for studying the resistance of tumors to T-cell-based cancer therapies. Restifo notes that if the genes are validated in clinical trials, then the data may eventually lead to more effective therapies for patients.
“If we can really understand the mechanisms by which tumors are resistant to immunotherapy, then we may be able to develop new therapies,†he said. In fact, in the future, this knowledge may accelerate a new class of drugs that can overcome them. These escape mechanisms of the tumor help the patient to experience complete remission."
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