A promising immunological pathway that shows promise to treat bone tumors has been discovered by investigators at Rice University. The finding, published in Proceedings of the National Academy of Sciences, has the potential to improve treatments for these stubborn tumors, which is one of the most prevalent forms of metastases in breast cancer patients.
According to the Centers for Disease Control and Preventation, of the more than 240,000 newly diagnosed cases of breast cancer in the U.S. each year, roughly one-quarter of those patients will experience metastatic disease.
“More than 70% of people with metastatic breast cancer will see the cancer cells move to bone, which can lead to skeletal-related events like bone pain, fractures, and hypercalcemia,” said Yixian Wang, a graduate student in the lab of Han Xiao who is a lead author on a study. “There are now several immunotherapies that can potentially benefit breast cancer patients with metastases, but they aren’t effective in patients with bone tumors.”
Checkpoint inhibitor immunotherapy is increasingly used for hard-to-treat tumors, but despite their broad efficacy, they have shown little effect for the treatment of bone metastases. The Rice team saw this as an unmet need and launched their research with the aim of finding an alternate treatment pathway.
“We thought there must be another novel checkpoint axis we could target for the breast cancer cells in bone,” said Xiao and associate professor of chemistry, biosciences, and bioengineering at Rice, “and we discovered a unique glyco-immune checkpoint axis in bone metastases that involves a protein called sialic acid-binding Ig-like lectin (Siglec)-15. We learned that it suppresses immune cells in the bone.”
Xiao and colleagues showed that the Siglec-15, which is significantly upregulated in the tumor microenvironment in bone cancer, plays a vital role in preventing the immune system from recognizing and attacking bone tumors. The reason current checkpoint inhibitors aren’t effective in treating these bone tumors is because they are mediated by protein-protein interactions that suppress immune cells.
“Siglec-15, however, is a glyco-immune checkpoint inhibitor,” Xiao points out. “Instead of binding to a protein, Siglec-15 binds to the sugars you find on the cell surfaces—and that’s how it can suppress the immune system. This is an entirely new type of immune checkpoint that offers great promise for future treatment for bone cancers.”
This finding provides a fertile road for further investigating glycol-immune checkpoint inhibitors and to discover which ones can effectively prevent bone tumors from evading immune recognition.
As part of their research, the investigators also injected mouse models of metastatic breast cancer with bone tumors with a monoclonal antibody that targets Siglec-15. This triggered an immune response that was so significant, the team saw the tumors diminish after only one or two doses of the antibody.
“It was really a striking finding,” says Wang. “I’m very excited about the potential therapeutic outcome for a therapy like this. This could be a very helpful treatment for breast cancer patients in the future.”
Future work will now focus on better understanding the biology of glycol-immune checkpoint pathways in the tumor microenvironment, as well as finding whether targeting Siglec-15 could be effective against other types of bone cancer.
