USC Study Explores New Insights into Innate Eesistance for Immunotherapies in Colorectal Cancer

A new study from the USC Norris Comprehensive Cancer Center has found evidence that targeting CD47, a protein that is part of the innate immune system, could be a key step in fighting colorectal cancer.

It is 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. The findings were just published in the Journal for ImmunoTherapy of Cancer.

Traditional immunotherapies, known as immune checkpoint inhibitors, have transformed cancer care by helping the body’s immune system fight cancer like it does other diseases. They do this by blocking immune checkpoints – proteins that act like brakes for the immune system to keep it from attacking healthy cells. Cancer cells exploit these proteins to evade detection by immune cells, but immune checkpoint inhibitors prevent that.

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, known as the innate immune system.

“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 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, 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.

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 a very 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.

Combining immunotherapies

To delve into the details of CD47’s role in colon cancer, researchers sequenced the DNA and RNA from 14,287 colorectal tumor samples stored within the Caris Life Sciences database. The researchers divided cases into two groups: those with high CD47 expression (above the median level) and those with low CD47 expression (below the median level). They then compared the two groups, looking for differences in immune signaling and other biological processes.

Higher expression of CD47 within a tumor was associated with higher oncogenic signaling, which means that tumors are growing and may be spreading. Higher CD47 expression was also linked to changes in several key immune pathways, including suppressing the signal used to activate macrophages, which would otherwise eliminate the cancer cells.

The researchers also found that higher levels of CD47 were associated with the formation of new blood vessels, a process called angiogenesis. In cancer research, angiogenesis is a red flag because it is typically a sign that tumors are growing larger.

Taken together, these findings point to CD47 as a top target for new colorectal cancer drugs. It could be used alongside one of more of the currently available therapies, including chemotherapy, angiogenesis inhibitors and adaptive immune checkpoint inhibitors, said Arai, who is now an assistant professor of clinical oncology at the St. Marianna University School of Medicine in Kawasaki, Japan.

“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,” said Lenz, who is also a professor of medicine and preventive medicine at the Keck School of Medicine.

Lenz, Arai and their team are also studying other methods of shrinking colorectal cancer tumors, including with compounds that stimulate macrophages to attack cancer cells.

About this research

In addition to Lenz and Arai, the study’s other authors are Francesca Battaglin, Jingyuan Wang, Sandra Algaze, Priya Jayachandran, Shivani Soni, Wu Zhang, Yan Yang, Joshua Millstein and Jae Ho Lo from the Norris Comprehensive Cancer Center, Keck School of Medicine of USC, University of Southern California; Nishant Gandhi, Joanne Xiu and Micharl W. Korn from Caris Life Sciences Inc.; Davendra Sohal from University of Cincinnati Medicine; Richard Goldberg from the West Virginia University Cancer Institute; Michael J. Hall from Fox Chase Cancer Center, Philadelphia, Pennsylvania; Aaron James Scott from the University of Arizona Cancer Center, Department of Medicine; Jimmy J. Hwang from GI Medical Oncology Levine Cancer Institute; Emil Lou from the University of Minnesota; Benjamin Weinberg from Georgetown University Medical Center; John Marshall from Georgetown University; and Sanjay Goel from Rutgers Cancer Institute of New Jersey.

This work was supported by the National Cancer Institute of the National Institutes of Health [P30CA014089]; the Gloria Borges WunderGlo Foundation; the Dhont Family Foundation; the Victoria and Philip Wilson Research Fund; the San Pedro Peninsula Cancer Guild; Ming Hsieh Research and the Daniel Butler Research Fund.