A team from Howard Hughes Medical Institute reported today in Science that more than 100 mutated tumor suppressor genes can prevent the immune system from spotting and destroying malignant cells in mice. According to Stephen Elledge, the study leader, “The shock was that these genes are all about getting around the immune system, as opposed to simply saying ‘grow, grow, grow!’”
Conventional wisdom had suggested that, for the vast majority of tumor suppressor genes, mutations allow cells to run amok, growing and dividing uncontrollably. But that explanation had some gaps. For example, mutated versions of many of these genes don’t actually cause rampant growth when put into cells in a petri dish. And scientists couldn’t explain why the immune system, which is normally highly proficient at attacking abnormal cells, doesn’t do more to nip new tumors in the bud.
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Elledge had a hunch that defective tumor suppressor genes were doing something more than ramping up cell growth. Starting with a list of 7,500 genes, his team used CRISPR to engineer thousands of tumor cells. Each lacked a functioning version of one of those genes. The researchers put the cells into two types of mice: those with an immune system, and those without. Then, the team studied the tumors that grew.
Genetic analyses revealed which mutated genes were abundant in the tumors, and likely playing a role in tumor formation. In mice with immune systems, defective tumor suppressor genes showed up frequently. This shows that those genes—about 30 percent of all tumor suppressor genes tested—work by enabling tumors to evade the immune system, Elledge says.
Elledge’s method revealed the many different genes that tumors can mutate to escape the body’s defenses. To explore possible mechanisms triggered by the mutations, the researchers zeroed in on a gene called GNA13. Mutating the gene protects cancer cells from the immune system’s T cells, creating a safe space for the tumor to thrive, the team found.