Response to cancer therapies is highly variable. While some cancers that have genomic defects, including microsatellite instability (MSI) and deficient DMA mismatch repair (dMMR) are understood to be more likely to activate the immune system, the mechanism underlying this response is still unclear.
Researchers from the Keck School of Medicine of USC have identified a genetic feedback loop in colorectal cancers that may explain one such mechanism. They recently published their work in Gastroenterology.
The team, led by Lin Zhang, PhD, professor and chair of oncology at the Keck School of Medicine, and Heinz-Josef Lenz, MD, associate director for clinical research at the USC Norris Comprehensive Cancer Center, focused on identifying the “role and mechanism of MSI-induced antitumor immunity and immunogenic cell death response.”
To do this, they used a combination of methods including createing a mouse model with transplanted tumor cells, immune cell assays and organoid data to elucidate the mechanism of action for the dMMR derived antitumor immune response.
Mice injected with tumor cells lacking a functional Mlh1, a gene that is involved with DNA repair, showed increased immune response that was tracked for cell signaling, behavior, and gene activity. Researchers identified Death Receptor 5 (DR5) and Ligase 3 (Lig3) as immune response mediators.
“We found that inactivating Mlh1 causes endoplasmic reticulum stress and Dr5–mediated apoptosis in syngeneic colorectal tumors,” the authors wrote. “Sustained immune response against Mlh1-deficient tumors requires nuclear Lig3–mediated release of extrachromosomal circular DNAs from apoptotic cells. A feedback Dr5/Lig3 amplification loop perpetuates apoptosis and immune cell activation in Mlh1-deficient syngeneic tumors.”
This continued immune response to dying tumor cells is critical for effective response to immune checkpoint inhibitor therapy, but it is not the complete story.
“We’ve gathered enough evidence to suggest that this feedback loop is an important piece of the puzzle,” said co-lead author Zhang. “Our hope is that these findings can someday help make cancers more visible to the immune system and more responsive to immunotherapy treatment.”
Validation of these results in humans is a necessary next step to get closer to the clinic. The team analyzed data from human patients, examining gene expression in colorectal cancers. They found that in patients with higher levels of DR5 and Lig3 activity, immune checkpoint inhibitor therapies were move effective at treating the cancer, and those patients were more likely to respond better to treatment.
“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.”
Moving forward, the team plans to explore the effectiveness of drugs that activate the DR5 pathway and investigate alternative methods for how to incorporate DR5 and Lig3 into personalized colorectal cancer therapies. They also note that, “Our results reveal a functional link between dMMR and antitumor immunity, which may be useful for improving immune checkpoint inhibitor therapy in tumors with different MMR statuses.”
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