Role of Inherited Genetic Variation in Cancer Immunity Elucidated

A new study has found that inherited genetic variation plays a role in who is likely to benefit from checkpoint inhibitors, which release the immune system's brakes so it can attack cancer. The study also points to potential new targets that could help even more patients unleash their immune system's natural power to fight off malignant cells.

"There are some factors that are already associated with how well the immune system responds to tumors," said Elad Ziv, co-senior author of the paper published yesterday in Immunity. "But what's been less studied is how well your genetic background predicts your immune system's response to the cancer. That's what is being filled in by this work: How much is the immune response to cancer affected by your inherited genetic variation?"

The study suggests that, for a range of important immune functions, as much as 20 percent of the variation in how different people's immune systems are able to attack cancer is due to the kind of genes they were born with, which are known as germline genetic variations.

"Rather than testing selected genes, we analyzed all the genetic variants we could detect across the entire genome. Among all of them, the ones with the greatest effect on the immune system's response to the tumor were related to interferon signaling. Some of these variants are known to affect our response to viruses and our risk of autoimmune disorders," said Davide Bedognetti, co-senior author of the paper. "As observed with other diseases, we demonstrated that specific genes can also predispose someone to have a more effective anti-cancer immunity."

The team identified variants in 22 regions in the genome, or in individual genes, with significant effects—including one gene, IFIH1, that is already well known for the role its variants play in autoimmune diseases as varied as type 1 diabetes, psoriasis, vitiligo, systemic lupus erythematosus, ulcerative colitis and Crohn's disease.

All told, the scientific team examined nearly 11 million gene variants to see how they matched with 139 immune parameters measured in patient tumor samples. But the 22 regions or genes identified in the new study are just the tip of the iceberg, the researchers said, and they suspect many more germline genes likely play a role in how the immune system responds to cancer.