Researchers at Dana-Farber/Boston Children's Cancer and Blood Disorders Center have developed a screening method that uses CRISPR-Cas9 to test the function of thousands of tumor genes in mice. Their research has revealed new drug targets that could potentially enhance the effectiveness of PD-1 checkpoint inhibitors.
The team, led by pediatric oncologist W. Nick Haining, reported in Nature today that deletion of the Ptpn2 gene in tumor cells made them more susceptible to PD-1 checkpoint inhibitors.
"PD-1 checkpoint inhibitors have transformed the treatment of many cancers," says Haining, senior author on the new paper, and also associate professor of pediatrics at Harvard Medical School and associate member of the Broad Institute of MIT and Harvard. "Yet despite the clinical success of this new class of cancer immunotherapy, the majority of patients don't reap a clinical benefit from PD-1 blockade."
That, Haining says, has triggered a rush of additional trials to investigate whether other drugs, when used in combination with PD-1 inhibitors, can increase the number of patients whose cancer responds to the treatment.
"The challenge so far has been finding the most effective immunotherapy targets and prioritizing those that work best when combined with PD-1 inhibitors," Haining says. "So, we set out to develop a better system for identifying new drug targets that might aid the body's own immune system in its attack against cancer.
"Our work suggests that there's a wide array of biological pathways that could be targeted to make immunotherapy more successful," Haining continues. "Many of these are surprising pathways that we couldn't have predicted. For instance, without this screening approach, it wouldn't have been obvious that Ptpn2 is a good drug target for the immunotherapy of cancer."
As part of the study, Robert Manguso, a graduate student in Haining's lab and first author on the paper, designed a genetic screening system to identify genes used by cancer cells to evade immune attack. He used CRISPR-Cas9 to systematically knock out 2,368 genes expressed by melanoma skin cancer cells. Manguso was then able to identify which genes, when deleted, made the cancer cells more susceptible to PD-1 blockade.
Using this approach, Manguso and Haining first confirmed the role of two genes already known to be immune "evaders" —PD-L1 and CD47, drug inhibitors that are already in clinical trials. They then discovered a variety of new immune evaders that, if inhibited therapeutically, could enhance PD-1 cancer immunotherapy. One such newly found gene of particular interest is Ptpn2.
"Ptpn2 usually puts the brakes on the immune signaling pathways that would otherwise smother cancer cells," Haining says. "Deleting Ptpn2 ramps up those immune signaling pathways, making tumor cells grow slower and die more easily under immune attack."