Dismantling pancreas cancer's armor

Pancreas cancer is notoriously impervious to treatment and resists both chemotherapy and radiotherapy. It has also been thought to provide few targets for immune cells, allowing tumors to grow unchecked. But new research from Fred Hutchinson Cancer Research Center shows that pancreas cancer "veils" itself from the immune system by recruiting specialized immune suppressor cells. The research team also found that removing these cells quickly triggers a spontaneous anti-tumor immune response.

The findings, published Feb. 20, 2014 in Gut, give hope for future immunotherapy strategies against this deadly and aggressive cancer.

"The take-home message is that there is a latent immune response against pancreas cancer that can be expressed if we remove its obstacles," said Sunil Hingorani, M.D., Ph.D., an associate member of the Clinical Research Division at Fred Hutch, who led the study. "Removing the suppressor cells creates a context that could enable an adoptive immune cell therapy against pancreas cancer."

Activating a T-cell response against the cancer

Pancreas cancer is nearly always diagnosed at very late stages, which has made its development hard to study. To gain insight into these aggressive tumors, Hingorani's team pioneered the development of a genetic mouse model of pancreas cancer. Previous work in the model led to their discovery of an enzyme that can make pancreas tumors more permeable to chemotherapy. The group turned again to this model to learn more about how pancreas tumors interact with the immune system.

From their earlier work, Hingorani's team knew that several different types of immunosuppressive cells infiltrate pancreas tumors. Together with immunologist Philip Greenberg, M.D., a member of Fred Hutch's Clinical Research Division, they have begun studying ways to target these inhibitory cells. As Ingunn Stromnes, Ph.D., the postdoctoral researcher co-mentored by Hingorani and Greenberg who spearheaded this latest study, watched pancreas tumors develop in mice, she saw that one cell type stood out. Descended from bone marrow cells and dubbed granulocyte-myeloid-derived suppressor cells (Gr-MDSCs), these cells jumped in number as pancreas tumors turned invasive. Stromnes discovered the pancreas tumors were orchestrating the accumulation of these suppressor cells by releasing a protein known as granulocyte macrophage colony-stimulating factor (GM-CSF), which attracted the Gr-MDSCs.

Strikingly, the Gr-MDSCs actively worked against T cells, a class of immune cell central to many immunotherapy strategies. T cells are often harnessed to fight tumors because they can recognize very specific molecules and destroy any cells expressing those molecules. But Gr-MDSCs prevented T cells from dividing and even induced their death.

Stromnes found this effect could be reversed, however, and the T-cell response activated, by depleting Gr-MDSCs. When she did so, she saw evidence not only that the T cells could now enter the tumors, but also that the tumors showed evidence of the type of cellular damage the T cells are designed to mete out.