Researchers at NYU Langone Medical Center and its Perlmutter Cancer Center have uncovered a critical pathway by which pancreatic cancer cells turn off the immune system charged with attacking them.

The findings appeared in a paper published online April 10 in the journal Nature Medicine.

The study, conducted in mice and including analyses of human cancers, found very high levels of two proteins – dectin–1 and galectin–9 – in pancreatic tumors. Their interaction prevented first–responder immune cells, called macrophages, from triggering reactions that kill cancer cells. Related analyses of human patient data linked elevated levels of galectin–9 to reduced survival in pancreatic ductal adenocarcinoma (PDA), although larger, confirmatory studies are needed, say the authors.

Perlmutter Cancer Center researchers used a mouse model of PDA, a disease that is usually fatal in patients within five years of diagnosis. They compared mice with pancreatic cancer that made dectin–1 against a group engineered to not make the protein, and determined that the mice without dectin–1 lived longer. The research team also found that treating mice with an antibody that blocked the galectin–9/dectin–1 interaction dramatically reduced tumor size and increased survival.

The new NYU Langone study revolves around the ability of immune cells to “decide” which cell types to become based on the type of invader encountered – including macrophages that arrive first at the sites of infection.

Macrophages of the M1 class effectively kill cancer cells, say the authors. However, if instead macrophages mature into the M2 class, they suppress anti–tumor responses. Pancreatic cancer cells are known to emit signals that shift the lineage of in–rushing macrophages from M1 to immune–suppressing M2. This effect has been linked in past studies to shorter survival in cancer patients, but how it happens is not entirely understood.

M1 and M2 macrophages each have protein receptors on their surfaces that let them receive signals from their surroundings. The new study revealed that pancreatic cancer cells not only send signals that make macrophages produce abnormal amounts of dectin–1 surface receptors, but also that make tumor cells themselves express high levels of galectin–9.

Galectin–9 turns on dectin–1, shifting macrophages to the M2 pathway and preventing them from fighting cancer, say the researchers. When mice bearing pancreatic tumors were injected with an antibody that prevents galectin–9 from docking into dectin–1, they developed M1 macrophages, which sent signals that dramatically increased the number of T cells capable of attacking the cancer cells.

Tumor size in mice injected with the antibody steadily decreased over time, while their survival increased. While only 25 percent of untreated mice were alive at 55 days, 90 percent of the mice treated with the galectin–9 antibody survived.

Checkpoint inhibitors are an emerging class of immunotherapies that have been approved for the treatment of several cancers. However, they have been ineffective in clinical trials against pancreatic cancer. When the study authors treated mice with a combination of antibodies against galectin–9 and the “checkpoint” protein, programmed death receptor 1, or PD1, they found that tumors were less than half the size of those treated with either antibody alone.

“Our results have potentially broad implications because macrophages with dectin–1 on their surfaces, and cells expressing galectin–9, infiltrate many cancer types,” says Donnele Daley, MD, a postdoctoral fellow in Miller’s lab, and first author of the current study along with Vishnu Mani, MD. Dr. Mani adds that “this could be a real game changer in the treatment of pancreatic cancer patients.”