Tumors use unexpected tricks to evade the immune system, according to new findings from researchers at the Brigham and Women’s Hospital in Boston. The team found that hundreds of cancer-linked genes play an unexpected role in causing disease than previously thought. Tumor suppressor genes (TSGs) have long been known to block cell growth, preventing cancerous cells from spreading. Mutations in these genes, scientists believed, allow tumors to flourish unchecked. This new research shows that more than 100 mutated TSGs can prevent the immune system from spotting and destroying malignant cells in mice.
This work is published in Science in the article, “The adaptive immune system is a major driver of selection for tumor suppressor gene inactivation.”
“These results reveal a fascinating and unexpected relationship between tumor suppressor genes and the immune system,” said Bert Vogelstein, MD, professor of oncology and cancer geneticist at the Johns Hopkins University School of Medicine and who was not involved in the research.
During tumorigenesis, tumors must evolve to evade the immune system. Typically, they do this by disrupting the genes involved in antigen processing and presentation or up-regulating inhibitory immune checkpoint genes.
Conventional wisdom had suggested that, for the vast majority of TSGs, mutations allow cells to grow and divide 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.
Starting with a list of 7,500 genes, the team performed in vivo CRISPR screens in syngeneic mouse tumor models to examine requirements for tumorigenesis—with and without adaptive immune selective pressure. In each tumor type tested, they wrote, “we found a marked enrichment for the loss of tumor suppressor genes in the presence of an adaptive immune system relative to immunocompromised mice.”
Nearly one-third of TSGs showed preferential enrichment, often in a cancer- and tissue-specific manner. This shows that those genes—about 30% of all TSGs tested—work by enabling tumors to evade the immune system, said Stephen Elledge, PhD, professor of genetics and of medicine at Harvard Medical School, and Howard Hughes Medical Institute investigator.
This method revealed that there are 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.
“The shock was that these genes are all about getting around the immune system, as opposed to simply saying ‘grow, grow, grow!’” said Elledge.
The idea that tumors can evade the body’s defenses is not new. In one major advance in cancer treatment over the last few decades, scientists uncovered that some tumors churn out proteins that switch off immune cells known to attack cancerous cells leading to the development of checkpoint inhibitors. The first checkpoint inhibitor was approved in 2011. However, the drugs work only in a minority of patients and cancer types. Elledge’s work may help explain why tumors have far more genetic tricks for fighting off the immune system than anyone had previously thought.
In addition, the authors noted, these results suggest that, “clonal selection of recurrent mutations found in cancer is driven largely by the tumor’s requirement to avoid the adaptive immune system.”
Their research paints a sobering picture of a quick and fierce evolutionary arms race between cancer cells and the immune system, Elledge said, with tumors having hundreds of potential ways to foil the body’s attack. But he suspects that many of these mutated genes act via similar strategies, a possibility his team can now examine in detail. If this proves to be the case, an intervention to block one evasion technique could potentially thwart others as well.
Overall, Elledge hopes his findings open new doors to treating cancer—by making it possible to uncover and stymie tumors’ new and different tricks. “There are a lot of genes that people can now study,” he said.
