Genome screen uncovers new targets for cancer immunotherapy

A new platform developed at Yale utilizes CRISPR technology to knock out genes individually and test which have the biggest impact on tumor response.

Immunotherapy has revolutionized the treatment of cancer in the last decade, yet many tumors do not respond to these new therapies. A new genome-wide screen of 20,000 human genes in T cells have turned up several new candidates to unleash the immune system’s ability to attack a variety of tumor types, Yale researchers report Aug. 22 in the journal Cell.

Immunotherapy is not effective in all patients and 70% to 80% don’t respond to treatment,” said Yale’s Sidi Chen, assistant professor of genetics and senior author of the study. “We asked: Why don’t we take one gene at a time and see which ones are responsible for tumor growth and might be targets for new therapies?”

Many immunotherapy treatments are based on inhibiting the gene PD1, which suppresses the ability of T cells to mobilize and attack cancer tumors. These therapies have dramatically increased survival of patients with some types of cancers, such as melanoma and lung cancer. Yet even in these cancers, only 30% to 40% of patients respond to immunotherapy alone. For most cancer types, the response rates are below 20% — and below 10% for some aggressive tumors.

The new platform developed at Yale utilizes CRISPR gene editing technology to knock out genes individually in mice to see which ones might have biggest impact on the immune system’s response to tumors. One of genes identified in the new research, DHX37, was found to suppress the response of CD8 “killer” T cells to tumors in mice. The researchers showed that mice bred to have triple negative breast cancer showed a significant reduction of tumors when DHX37 was edited from their genomes.

Once we eliminated this brake on the immune system, the killer T cells could go crazy attacking tumors,” Chen said.

Chen said his laboratory is now studying several other genes discovered during the screens to assess their impact on various types of tumors and developing new immunotherapeutic agents against these targets.

Yale’s Matthew B. Dong, Guangchuan Wang, Ryan D. Chow, and Lupeng Ye are co-first authors of the study.

Chen is affiliated with Yale’s Department of Genetics, the Yale Cancer Center, the Yale Stem Cell Center, the Yale Center for Biomedical Data Science, and the Systems Biology Institute and Center for Cancer Systems Biology at West Campus.

Funding for the study primarily came from the National Institutes of Health.


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Part of the In Focus Collection: Fighting for hope: breast cancer research at Yale

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