Novel Genetic Screening a Boon to Cancer Immunotherapy

Immune checkpoint inhibitors are drugs that are used in immunotherapy to treat cancer. However, checkpoint inhibitors like PD-1 are effective only in a minority of cancer patients. Researchers have been trying to identify if other drugs, when combined with PD-1, are able to destroy cancer cells in more number of patients. A novel screening system developed by a team from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center using CRISPR-Cas9has paved the way for the discovery of new drug targets that may aid in cancer immunotherapy. Cancer Immunotherapy and Checkpoint Inhibitors

Immunotherapy is a commonly used treatment option for cancer. It is also called biotherapy or biological therapy. Here the patients’ own immune system is used to fight the cancer. This is done by either stimulating the immune cells to work harder or by introducing man-made immune proteins in the patient.

An individual’s immune system is responsible for destroying all foreign materials or organisms that enter the body. It does so with the help of cells called immune cells. Immune cells to some extent protect the body from cancer also. However, this is limited, as the immune cells do not always recognize the cancer cell as a foreign material. This is because the cancer cells are not very much different from normal body cells or the immune response is not strong enough to destroy the cancer cells. Sometimes the cancer cells themselves apply a “brake” to evade the immune attack.

Checkpoint Inhibitors are drugs that switch off the “brakes”, which helps the immune cells to recognize and attack the cancer. Examples of these include PD-1 and CTLA-4.

However, PD-1 is effective in only a minority of cancer patients. This study published in Nature was able to identify targets that made the cancer cells more susceptible to PD-1 using a novel screening method.

Novel CRISPR-Cas9 in-vivo Genetic Screening Method

Melanoma (skin cancer)cells were genetically modified to express Cas9 enzyme that cuts the DNA. 2,368 genes expressed in melanoma cells were tested to identify if they increase susceptibility of cancer cells to PD-1 or help in evasion. CRISPR was used to knock out each one of the 2,368 genes. Once the genes were knocked out, they were put into a mouse to crate a tumor. Each mouse model was further provided immunotherapy (PD-1 checkpoint inhibitors) to help fight the cancer cells. If a maximum number of cancer cells were destroyed, it meant that the gene that was knocked out in that mouse model made the cancer cells more susceptible to the PD-1 immunotherapy.

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Using this screening method, several previously undiscovered immunotherapy targets were discovered. Deletion or knocking out of Ptpn-2 gene markedly increased the response of the tumors to immunotherapy. This in turn means that if a drug is invented to specifically block or delete the Ptpn-2 gene in cancer cells, then the cancer cells may easily be destroyed in a majority of patients through immunotherapy.

Senior author Haining said "Deleting Ptpn-2 ramps up those immune signaling pathways, making tumor cells grow slower and die more easily under immune attack."

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Future prospects

• In vivo genetic screens in tumor models can identify new immunotherapy targets.
• May be applied to all cancers including renal, colon, lung and other cancers.
• Development of drugs that induce a loss of function in the Ptpn-2 gene.

Reference:

1. Manguso, R. T., Pope, H. W., Zimmer, M. D., Brown, F. D., Yates, K. B., Miller, B. C., Haining, W. N. (2017). In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. doi:10.1038/nature23270

Source-Medindia