Cancer Immunotherapy: CRISPR Screen Identifies Top 100 Essential Genes

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Cancer Immunotherapy: CRISPR Screen Identifies Top 100 Essential Genes
The DNA double helix rests on a field of ACGTs and binary numbers. [Jonathan Bailey/National Human Genome Research Institute]

Immunotherapy can be highly effective against advanced cancers in some patients, but in other cases treatment doesn’t work. To try to understand the genetic basis of these differing responses, scientists [...] developed a genome-scale CRISPR/Cas9 screen that allowed them to knock out every single gene in a melanoma cell line and then systematically test each gene for its effect on T-cell responses against the melanoma. Using this "two-cell type" (2CT)-CRISPR assay, the researchers, [...], identified more than 100 "essential" genes that were required in the melanoma line for T cells to effectively engage with and kill the cells. When these genes were knocked out, the tumor cells were more able to resist exposure to T cells that had been engineered specifically to recognize tumor-associated antigens.
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CRISPR/Cas9 screens have previously been used to identify genes that play key roles in cancer cell proliferation, drug resistance, and metastasis [..]. To identify which genes in tumors are requisite for the "effector function of T cells," the team developed the 2CT-CRISPR assay, consisting of human T cells as effectors and melanoma cells as targets, to evaluate the effects of individual gene knockouts on cancer cell susceptibility to T-cell killing. Many of the hundred or so genes identified were directly involved in cytokine release, or in antigen processing and presentation, but dozens of the genes identified were not known to be required for cytotoxic T-cell-based immunotherapy.
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“This indicated that the loss of genes that T cells need to kill cancer cells might be at least partially responsible for why immunotherapy fails in some patients,” [...] “However, we were really surprised to find dozens of tumor genes that had major impacts on tumor cell survival, which hadn’t previously been linked with the ability of T cells to kill target cancer cells.  Exploring potentially new signaling pathways mediated by these genes could help us to understand how T cells interact with cancer cells to bring about cell death, and how cancers can evade the immune system.”
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The study findings also indicate that the success of cancer immunotherapy depends on the interplay between a far greater number of genes than previously thought, [..].  “A deeper understanding of how T cells interact with potential target cells could also help us to develop more effective treatments for infectious and autoimmune diseases.”
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New Reference  CRISPR Screen Identifies Top 100 Essential Genes for Cancer Immunotherapy

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