How do faulty genes drive cancer? There's a surprising immune connection, study finds

Mutations in tumor-suppressing genes are known to drive cancer, but how? Scientists long believed that the mutations prompted the cancerous cells to grow unchecked. But a new study out of Howard Hughes Medical Institute suggests the story is more complicated than that.

The Howard Hughes team discovered that more than 100 mutated cancer-suppressor genes don’t act directly on cancer cells to cause them to grow, but rather they block the immune system from recognizing and destroying tumors. They published their findings in Science.

The study started with a hunch from Stephen Elledge, Ph.D., professor of genetics Harvard Medical School and Brigham and Women’s Hospital and Howard Hughes researcher. Scientists have long struggled to explain why mutated tumor-suppressor genes don’t cause cancer to grow in lab dishes, and, more broadly, why the immune system can recognize and eliminate viruses and other foreign invaders but not cancer.

Elledge’s team used CRISPR to engineer tumor cells that lacked functioning versions of any one of 7,500 tumor-suppressor genes. Then they put the cells into mice, only some of which had intact immune systems.

They used genetic analysis to determine which mutated genes were playing a role in tumor formation. By comparing the immune-deficient mice with the intact animals, they discovered that one-third of tumor-suppressor genes work via immune evasion.

One particular gene, GNA13, elucidated how this process works. By studying the gene closely, the researchers discovered that mutations cloak cancer cells so the immune system’s T cells can’t detect them.

“The shock was that these genes are all about getting around the immune system, as opposed to simply saying ‘grow, grow, grow!’” Elledge said in a statement.

RELATED: Vanderbilt scientists offer new clues for developing cancer drugs against mutant tumor suppressor protein

Mutated tumor-suppressor genes and the proteins they produce are popular targets in cancer drug development, but some have been frustratingly elusive, such as p53. Earlier this month, a team at Vanderbilt University published research showing that a chromosomal abnormality called aneuploidy was common in cells with mutant p53, a finding they thought could inform drug development aimed at targeting the rogue protein.

Earlier this summer, scientists from Karolinska Institutet in Sweden and Aileron Therapeutics showed they could reactivate normal p53 by inhibiting another protein, MDM2. They suggested the approach be used alongside drugs that inhibit immune checkpoints.

Elledge believes his study provides a list of tumor-suppressor genes that scientists can now study to better understand how cancer evades the immune system. It’s possible tumors employ hundreds of immune-evasion techniques, he said, and uncovering those pathways could inspire new methods for treating cancer.