A protein that makes pancreatic stem cells invisible

Inside tumors, cancer stem cells can proliferate into new cancerous tissue. These cells are metastatic, resistant to chemotherapy, and extremely skilled at hiding from the immune system to avoid attack. “They are the root of the tumor,” said Bruno Sainz Jr., a molecular oncologist at the Sols-Morreale Biomedical Research Institute (IIBM). “If you are able to attack and eliminate these cells, then you could potentially cure the cancer.”

Sainz Jr.’s group has been studying cancer stem cells in pancreatic cancer, one of the deadliest cancers worldwide (1). Immunotherapies don’t work for pancreatic cancer as it’s considered a “cold tumor” without the presence of infiltrated immune cells, yet scientists haven’t understood what allows these cancer stem cells to remain hidden.

If you are able to attack and eliminate these cells, then you could potentially cure the cancer.
– Bruno Sainz Jr., Sols-Morreale Biomedical Research Institute

In a new study in mice, Sainz Jr.’s team showed that pancreatic cancer stem cells evade the immune system by producing peptidoglycan recognition protein 1 (PGLYRP1), a protein usually produced by neutrophils to attack bacteria (2). “It's a really awesome defense mechanism that the cancers themselves have to make themselves not visible,” said Sainz Jr. “It's very, very surprising. We did not expect any of this.”

When they eliminated PGLYRP1 from cancer stem cells, immune cells successfully recognized and destroyed them.

To find out how PGLYRP1 conceals cancer stem cells, the research team studied a mouse model of pancreatic cancer and patient-derived xenographs. They found that PGLYRP1 protects cancer stem cells by binding to a receptor (they’re still working to identify which one) that induces the killing of activated T cells that would normally attack the tumor. As for why cancer stem cells can produce the protein, Sainz Jr. said it’s likely an epigenetic mechanism that’s turned on in cancer stem cells and not in other types of cancer cells.

Revealing how these pancreatic cancer stem cells evade the immune system could allow for new treatments that inhibit PGLYRP1 and prevent the cells from hiding. “It gives us hope that maybe one day immunotherapy will be a reality for patients with pancreatic cancer,” said Sainz Jr.

For now, they plan to develop a vaccination approach against the protein and test it out in mice to see whether it allows the immune system to target the tumor cells and prevent the development of pancreatic cancer. “[PGLYRP1 is] present very early on in the development of pancreatic cancer, and also present very late,” said Sainz Jr. “It’s probably very important from the very early stages of pancreatic cancer development, so that the cancer stem cells can avoid the immune system and then perpetuate and facilitate the development of the tumor over time.”