A subset of cancers, known as microsatellite instability (MSI) and deficient DNA mismatch repair (dMMR) cancers, are more visible to the immune system than others. Because their DNA repair systems are defective, these tumors are more likely to be recognized and attacked by immune cells and tend to respond better to immunotherapy. But scientists do not fully understand why.
Now, the answer is coming into focus. Researchers from the Keck School of Medicine of USC discovered a biological feedback loop that helps the immune system recognize and attack colorectal cancers with MSI or dMMR. In mice, they found that two genes—Death Receptor 5 (DR5) and Ligase 3 (Lig3)—help drive a cycle of tumor cell death and immune system activation. They also found that human tumors with higher DR5 and Lig3 activity were more likely to respond to immune checkpoint inhibitors, a type of cancer immunotherapy.
The study, funded in part by the National Institutes of Health and just published in the journal Gastroenterology, may suggest a way to make immunotherapy more effective against cancers that respond poorly to treatment.
"We've gathered enough evidence to suggest that this feedback loop is an important piece of the puzzle," said lead author Lin Zhang, PhD , professor of medicine and the Mark A., J. Ruth and Stillman F. Sawyer Chair of Oncology at the Keck School of Medicine. "Our hope is that these findings can someday help make cancers more visible to the immune system and more responsive to immunotherapy treatment."
A positive feedback loop
To investigate what makes MSI and dMMR cancers different, Zhang and his colleagues created a mouse model of the disease by disabling a key DNA repair gene in tumor cells. They then implanted the altered cells into healthy mice to watch the immune response unfold.
As the mice mounted an immune response to the tumors, the researchers tracked changes in cell signaling, cell behavior and gene activity. Two genes—DR5 and Lig3—emerged as key players.
The DNA repair defect caused the tumor cells to increase activity of the DR5 gene, triggering their own destruction. As the cells died, they released extrachromosomal circular DNA (eccDNA), small circular pieces of DNA that are separate from the cell's main genetic material. More eccDNA was released when the Lig3 gene was highly active. The eccDNA, in turn, activated a broader immune response, creating a positive feedback loop that helped the immune system mount an ongoing attack against the tumor.
To validate their findings, the researchers then analyzed data from human patients. Looking at gene expression in colorectal cancers, they found that tumors with higher levels of DR5 and Lig3 activity responded better 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," Zhang said. "That suggests we're uncovering a mechanism that could be clinically relevant."
Boosting the immune response
Looking ahead, the researchers aim to explore whether drugs that activate the DR5 pathway or increase eccDNA release could make immunotherapy more effective. They also plan to investigate whether DR5 and Lig3 could help personalize treatment choices by predicting who is most likely to benefit from immunotherapy.
More research is needed before these approaches can be tested in patients, including studies of human colorectal tumor cells. Zhang will continue to work with Heinz-Josef Lenz, MD , associate director for clinical research and co-leader of the Gastrointestinal Cancers Program at the USC Norris Comprehensive Cancer Center. Lenz, a coauthor of the study, contributed clinical expertise and access to patient datasets that allowed the team to compare their laboratory findings with real-world outcomes.
The findings may also have implications for other MSI and dMMR cancers, including some ovarian and endometrial cancers, which Zhang and his team hope to explore.
About this research
In addition to Zhang and Lenz, the study's other authors are Suisui Hao, Yoshiaki Sato, Francesca Battaglin, Karam Ashouri. Zhaojin Liu, Xinyan Lu and Jian Yu from the Department of Medicine and the USC Norris Comprehensive Cancer Center, Keck School of Medicine of USC, University of Southern California; Yi-Jun Wang, Darleny Lizardo and Robert E. Schoen from the Hillman Cancer Center, University of Pittsburgh School of Medicine; and Joanne Xiu and Matthew Oberley from Caris Life Sciences, Phoenix, Arizona.
This work was supported in by the National Institutes of Health [R01CA236271, R01CA247231, R01CA248112, R01CA215481, R01CA260900] and start-up funds from the Keck School of Medicine of USC. The work used shared resources supported in part by the National Cancer Institute [P30CA047904, P30CA014089].
