Researchers led by Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have shown for the first time exactly how immature neutrophils are hijacked by pancreatic cancers to drive immunosuppression and treatment resistance.

Their findings are published in Cancer Discovery in a paper titled, “Cell-autonomous Cxcl1 sustains tolerogenic circuitries and stromal inflammation via neutrophil-derived TNF in pancreatic cancer.”

“We have shown that KRAS-TP53 genomic co-alteration is associated with immune-excluded microenvironments, chemoresistance, and poor survival in pancreatic ductal adenocarcinoma (PDAC) patients,” wrote the researchers. “By treating KRAS-TP53 cooperativity as a model for high-risk biology, we now identify cell-autonomous Cxcl1 as a key mediator of spatial T-cell restriction via interactions with CXCR2+ neutrophilic myeloid-derived suppressor cells in human PDAC using imaging mass cytometry.”

The paper describes a previously unrecognized signaling circuit in pancreatic cancer that instigates immunosuppression and tumor-promoting inflammation in the pancreatic tumor microenvironment.

This is the first study to implicate immunosuppressive signaling from immature neutrophils—the earliest sentinels in developing pancreatic cancer—in this process, explained Jashodeep Datta, MD, associate director of translational research at the Sylvester Pancreatic Cancer Research Institute.

“It suggests neutrophils are a dominant actor in this circuit. This is the first description of how cancer cells talk with neutrophils and how neutrophils are major actors in this immunosuppressive inflammatory drama in the pancreatic tumor microenvironment,” said Datta.

The research team, Datta said, is “creating a road map to target each element of these molecular dots” to thwart this inflammatory process and overcome therapeutic resistance.

Nipun Merchant, MD, the founding director of the Sylvester Pancreatic Cancer Research Institute and a co-author of the paper, said the research “will pave the way to the ultimate goal of clinical studies, so that our findings can be directly translated to improve patient care.”

Datta said clinical trials will attempt to target the immunosuppressive pathway from numerous angles.

“We’re collaborating with multiple groups across the country to make this happen and are developing a novel nanoengineering platform to target neutrophils without killing them so we can target the tolerogenic [immunosuppressive] signaling mechanisms within neutrophils,” he said.

The Sylvester team collaborated with researchers in different disciplines at the Miller School, including the departments of microbiology and immunology, the Diabetes Research Institute, and Public Health Sciences. They also worked with colleagues at other medical schools and cancer centers, including Johns Hopkins, the University of Pennsylvania, and Harvard.

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