Researchers from the Keck School of Medicine of USC announced on July 16 that they have discovered a biological feedback loop that helps the immune system recognize and attack colorectal cancers with microsatellite instability (MSI) or deficient DNA mismatch repair (dMMR). These types of tumors are more visible to the immune system due to defective DNA repair systems, which makes them more likely to respond to immunotherapy. However, the mechanisms behind this heightened visibility were not fully understood until now.
The study, published in Gastroenterology and funded in part by the National Institutes of Health, found that two genes—Death Receptor 5 (DR5) and Ligase 3 (Lig3)—play a key role in driving a cycle of tumor cell death and immune activation. In mouse models where a critical DNA repair gene was disabled, researchers observed increased activity of DR5 leading to tumor cell destruction. As these cells died, they released extrachromosomal circular DNA (eccDNA), especially when Lig3 activity was high. The release of eccDNA triggered a broader immune response, creating a positive feedback loop against the tumor.
To confirm their findings, researchers analyzed data from human patients with colorectal cancer. They found that tumors exhibiting higher levels of DR5 and Lig3 activity were more responsive to treatment with immune checkpoint inhibitors. "One of the most encouraging parts of the study was seeing that the same signals showed up in patient tumors," said Zhang. "That suggests we're uncovering a mechanism that could be clinically relevant."
Looking forward, researchers plan to investigate whether drugs targeting DR5 pathways or increasing eccDNA release could enhance immunotherapy effectiveness for cancers less responsive to current treatments. They also intend to explore whether DR5 and Lig3 could serve as biomarkers for personalizing immunotherapy choices.
Further research is required before these approaches can be tested clinically; future studies will focus on human colorectal tumor cells. Zhang will continue collaborating with Heinz-Josef Lenz, MD, associate director for clinical research at USC Norris Comprehensive Cancer Center, who contributed clinical expertise and access to patient datasets for comparing laboratory results with real-world outcomes.
The team also plans to examine whether these findings apply beyond colorectal cancer—to other MSI and dMMR cancers such as certain ovarian and endometrial cancers.
