Researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center (Boston, MA, USA) have recently developed a novel in vivo genetic screening approach, utilizing CRISPR-Cas9 genome editing technology in transplantable tumours in murine models treated with immunotherapy to discover previously undescribed immunotherapy targets.
The team revealed promising new drug targets that could potentially enhance the effectiveness of PD-1 checkpoint inhibitors, which are employed in cancer immunotherapy. The findings of the paper indicated 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,” commented senior author of the paper, W.Nicholas Haining (Dana-Farber Cancer Institute). “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.”
Therefore, this has prompted additional trials investigating whether certain drugs, when used in conjunction with PD-1 inhibitors, may increase the number of patients who respond positively 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 continued. “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 added. “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.”
The team tested 2368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. They recovered the known immune evasion molecules PD-L1 and CD47 and confirmed that defects in inteferon-γ signalling caused resistance to immunotherapy.
Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signalling, antigen presentation and the unfolded protein response. Additionally, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression.
“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.”
With the new in vivo screening approach in hand, Haining’s team is quickly scaling up their efforts to search for additional novel drug targets in unanticipated pathways that could boost immunotherapy.
Furthermore, they are expanding their approach to move from screening thousands of genes at a time to eventually be able to screen the whole genome, and to move beyond melanoma to colon, lung, renal carcinoma and more.
“We’re thinking hard about what a Ptpn2 inhibitor would look like,” concluded Haining. “It’s easy to imagine making a small molecule drug that turns off Ptpn2.”