A novel protective role of PYDC5 in colorectal cancer

Summary: Colorectal cancer is the second most deadly cancer in the US. Known risk factors for developing colorectal cancer are genetic mutations as well as environmental triggers and inflammation. While systemic inflammation is a marker for poor prognosis, local inflammation with immune cell infiltration can be associated with a better prognosis in colorectal cancer. Therefore, a better understanding of the readiness of the immune system to locally fight against emerging cancer cells determines colorectal cancer occurrence and progression and compelling evidence supports that modification and priming of the tumor immune microenvironment is an emerging and efficient strategy for the development of novel colorectal cancer therapies. We recently discovered PYDC5, which functions as an inhibitor for the dsDNA-induced AIM2 inflammasome. We now discovered that PYDC5 is expressed in a rare intestinal macrophage population, but that expression is cancer stage-dependently significantly reduced in colorectal cancer patients compared to matched controls. Conversely, macrophage-specific expression of PYDC5 in mice strongly protects from induced and spontaneous colorectal cancer, suggesting that impaired PYDC5 expression skews intestinal homeostasis and promotes colon tumorigenesis. Our preliminary data further imply that an inflammasome-independent, but type I interferon dependent mechanism is involved and that PYDC5 assembles into a novel nuclear signaling complex to promote a unique type I interferon signature to shape the intestinal immune cell and microbiome composition. The research proposed in this MPI application will elucidate the functional consequences from PYDC5 expression on intestinal homeostasis and colorectal cancer in induced and spontaneous models of colorectal cancer, will define the underlying molecular mechanisms by which PYDC5 shapes the tumor immune microenvironment to protect from colorectal cancer, and will functionally define the rare PYDC5+ intestinal macrophage cell population. Collectively, we expect that our research will uncover novel protective molecular mechanisms and expand our knowledge on type I interferon signaling, which can be exploited for the development of novel therapies that positively impact the quality of life of colorectal cancer patients. Project Number: 1R01CA301129-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Andrea Dorfleutner (+1 co-PI) | Institution: CEDARS-SINAI MEDICAL CENTER, LOS ANGELES, CA | Award Amount: $679,353 | Activity Code: R01 | Study Section: Basic Cancer Immunobiology Study Section[BCIB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11294619