Tumor-associated immune cells prevent first-line chemotherapy in pancreatic cancer

ANN ARBOR, Michigan – A first-line chemotherapy drug administered to patients with pancreatic cancer is made less effective because similar compounds released by tumor-badociated immune cells block the action of the patient. drug, according to a study conducted by the Rogel Cancer Center of the University of Michigan.

Gemcitabine chemotherapy is an anti-metabolite. This looks like the normal metabolites absorbed by the cell, but once inside, it kills the cell by disrupting its functions – like a Trojan horse. In pancreatic cancer, tumor immune cells release metabolites almost identical to gemcitabine, which block the drug's activity in malignant cells, the researchers found.

This information could be used to predict which patients will respond to treatment with gemcitabine, as well as to shed new light on other types of cancer where immune cells could play an important role in resistance to chemotherapy, according to the findings. recently published in Cell metabolism.

"Why does gemcitabine work well enough in some cancers, but not in pancreatic cancer, that is the big question my lab was trying to answer," says lead author of the study , Costas Lyssiotis, Ph.D., Assistant Professor of Molecular and Integrative Physiology at the UM School of Medicine.

Pancreatic cancer is one of the most deadly types of cancer. He is generally aggressive and does not respond well to traditional chemotherapy and radiotherapy treatments. And while progress has been made in recent years, five-year survival rates are still one-digit.

"Malignant cells often only account for about 10% of a tumor," says the study's first author, Christopher J. Halbrook, Ph.D., a postdoctoral researcher at Lyssiotis Lab. "The remaining 90% are other types of cells that support the growth of this tumor – structural cells, blood vessels, and immune cells." Our work has focused on the interaction between malignant cells and immune cells. "

There are often many contingents of immune cells called macrophages in pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer. And while macrophages were known to prevent the activity of gemcitabine chemotherapy, it was unclear exactly how immune cells did.

Lyssiotis and colleagues at U-M University and Scotland studied the interaction between malignant cells and tumor-badociated macrophages. They discovered that immune cells release a multitude of compounds called pyrimidines, which are metabolized by malignant cells.

One of these compounds, deoxycytidine, has a chemical structure very similar to gemcitabine and directly blocks the activity of the chemotherapy drug in malignant cells.

"Deoxycytidine basically supplants gemcitabine," said Lyssiotis, adding that the physiological reason underlying the release of pyrimidines by immune cells was still unclear.

After genetically and pharmacologically reducing the number of tumor-badociated macrophages in the mouse, the team showed that the tumors were less resistant to gemcitabine, making it easier to make tumors of patients more sensitive to chemotherapy.

The researchers also examined data from patients with pancreatic cancer and found that patients whose tumors had fewer macrophages responded better to treatment.

"When we think of personalized medicine, we often think about what's going on inside the malignant cells, the specific genetic mutations that a patient's tumor may have," says Lyssiotis. "In our case, we think about the question," What does this tumor look like? What does his cell ecosystem look like? "And we hope to be able to use an understanding of the interaction between different cell types to develop new treatment approaches."

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Other authors: Corbin Pontious, Ilya Kovalenko, Laura Lapienyte, Stephan Dreyer, Ho-Joon Lee, Galloway Thurston, Yaqing Zhang, Jenny Lazarus, Peter Sajjakulnukit, Hanna S. Hong, Daniel Kremer, Barbara S. Nelson, Samantha Kemp, Samantha Kemp, Li Chang, David Chang, Andrew Biankin, Jiaqi Shi, Timothy L. Frankel, Howard Crawford, Jennifer P. Morton, Marina Pasca di Magliano

Lyssiotis is a patent inventor relating to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting of GOT1 as a therapeutic approach.

Reference: Pyrimidines released by macrophages inhibit treatment with Gemcitabine in pancreatic cancer, Cell metabolism, doi: 10.1016 / j.cmet.2019.02.001

University of Michigan Rogel Cancer Center, http: // www.rogelcancercenter.org

Michigan Health Lab, http: // www.MichiganHealthLab.org

Michigan Cancer Tracking Line in Medicine, 800-865-1125