2 weeks Ago By John Sterling
Researchers from the USC Norris Comprehensive Cancer Center and collaborators report that they have found evidence that targeting CD47, a protein that is part of the innate immune system, could be a key step in fighting colorectal cancer. Their findings represent one of the first indications that targeting part of the innate immune system, combined with traditional immunotherapy drugs which work on the adaptive immune system, could be more effective in fighting colorectal cancer, according to the scientists, who published their work, “ ” in the . Until recently, immunotherapies only targeted the body’s learned immune response once cancer cells had already slipped by the body’s first line of defense against disease—the innate immune system—explain the researchers.
“Up until now, immune checkpoint inhibitors targeting the adaptive immune system have been the mainstream in immunotherapy,” said first author Hiroyuki Arai, MD, PhD, a former postdoctoral researcher at the USC Norris Comprehensive Cancer Center, part of the Keck School of Medicine of USC. “But in our current study, we focused on CD47, a checkpoint molecule in the innate immune system.” The researchers knew colorectal cancer cells use the immune checkpoint CD47 to dodge macrophages (the innate immune cells that would otherwise target and destroy them).
But how exactly do cancer cells manipulate CD47, and what could this mean when it comes to treating colon cancer? In the present study, funded in part by the National Institutes of Health, researchers analyzed DNA and RNA from 14,287 colorectal cancer tumors to answer those questions. They compared tumors with higher levels of CD47 expression to those with lower levels, finding that higher levels were linked to more aggressive tumors, more activated cancer pathways, and more immune cells inside the tumor. “In CD47-high tumors, the proportion of consensus molecular subtypes 1 and 4 was significantly higher than in CD47-low tumors.
The expression levels of damage-associated molecular pattern-related genes showed a positive correlation with CD47 expression levels,” the investigators wrote. “Major oncogenic pathways, such as mitogen-activated protein kinase, phosphoinositide 3-kinase, angiogenesis, and transforming growth factor beta, were significantly activated in CD47-high tumors. Additionally, the expression levels of a panel of adaptive immune checkpoint genes and estimates of immune cells constituting the tumor microenvironment (TME) were significantly higher in CD47-high tumors.
CD47 expression in CRC was associated with the activation of several oncogenic pathways and an immune-engaged TME. Our findings may provide valuable information for considering new therapeutic strategies targeting innate immune checkpoints in CRC.” Those findings suggest that developing an immune checkpoint inhibitor drug that can block the activity of CD47 could improve outcomes for colon cancer patients, many of whom are not well served by existing immunotherapy drugs.
“The most important takeaway is this data suggests that CD47 is an attractive target for drug development,” said senior author Heinz-Josef Lenz, MD, deputy director for research programs and co-director for the Rosalie and Harold Rae Brown Center for Cancer Drug Development at the USC Norris Cancer Center. “The key is to develop an antibody or an engineered immune cell that can inhibit CD47 signaling, but it has to be used in combination with other drugs. The right combination is not clear yet, so more research is needed,” continued Lenz, who is also a professor of medicine and preventive medicine at the Keck School of Medicine.
Lenz and the rest of the team are also studying other methods of shrinking colorectal cancer tumors, including with compounds that stimulate macrophages to attack cancer cells. Also participating in the research were scientists from Caris Life Sciences, University of Cincinnati Medicine, West Virginia University Cancer Institute, Fox Chase Cancer Center, University of Arizona Cancer Center, GI Medical Oncology Levine Cancer Institute, University of Minnesota, Georgetown University Medical Center, and the Rutgers Cancer Institute of New Jersey..
