Sylvester Researchers Identify Neutrophils as Major Culprits in Treatment Resistance of Pancreatic Cancer

Investigators at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have described a previously unrecognized signaling circuit in pancreatic cancer that instigates immunosuppression and tumor-promoting inflammation in the pancreatic tumor microenvironment, ultimately creating treatment resistance.

The central regulator of this treatment resistance is neutrophil-derived TNF signaling; indeed, immature neutrophils are the earliest sentinels in a developing pancreatic cancer, but this innovative work shows exactly how they are hijacked by pancreatic cancers to drive immunosuppression and treatment resistance. The work is highly relevant, important and novel, and has been published in one of today’s most prestigious scientific journals, Cancer Discovery.

“The findings in this paper are critical to our knowledge of one of the most treatment-resistant cancers — pancreatic cancer,” said Jashodeep Datta, M.D., senior author of the study, associate director of translational research at the Sylvester Pancreatic Cancer Research Institute and the DiMare Family Chair in Immunotherapy at the Miller School, whose laboratory at Sylvester led the research. “Our research connects the molecular dots between the high-risk tumor genotypes that exist in pancreatic cancer and the specific molecular and cellular culprits — the immature neutrophils — that are involved in creating immunosuppressive networks in the pancreatic tumor microenvironment.

“Not only are we creating a roadmap to target each element of these molecular dots, but we are focused on thwarting inflammatory signaling from immature neutrophils, which has never been identified before, in order to overcome therapeutic resistance in pancreatic cancer,” Dr. Datta said.

Cancer Discovery is one of the most respected basic and translational science cancer journals, with an impact factor of nearly 40.

“It only accepts publications that are truly novel, innovative and at the highest echelons of cancer discovery,” said Nipun Merchant, M.D., founding director of the Sylvester Pancreatic Cancer Research Institute. “This study identifies a novel mechanism of communication between tumor cells and immune cells that promotes a treatment-resistant microenvironment. Getting published in this high-profile journal is a reflection of the cutting-edge research going on at Sylvester and will pave the way to the ultimate goal of clinical studies, so that our findings can be directly translated to improve patient care.”

“We are proud of the significant contributions Dr. Datta is making to the field of immunotherapy and pancreas cancer,” said Stephen D. Nimer, M.D., director of Sylvester and the Oscar de la Renta Endowed Chair in Cancer Research. “As an NCI-designated cancer center, we are responsible for shaping the next generation of cancer researchers. Our investment in junior investigators like Jash Datta, through intramural funding awards and protected time for research, is critical to our mission to make discoveries and change the landscape of cancer care for decades to come. We are enthusiastic to see the impact he will continue to make in this field.”

Immature Neutrophils ‘Major Actors’ in Immunosuppressive Signaling

This is the first study to implicate immunosuppressive (also called tolerogenic) signaling from immature neutrophils, which are a very important arm of the immune system.

“It suggests neutrophils are a dominant actor in this circuit,” Dr. Datta said. “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.”

Making the discovery required collaborating with different disciplines at the Miller School, including the Department of Microbiology and Immunology, the Department of Public Health Sciences and the Diabetes Research Institute, and working with other medical schools and cancer centers, including Johns Hopkins, the University of Pennsylvania and Harvard University.

“In order to do super high impact factor translational research, you can’t work in a vacuum,” said the study’s first author Anna Bianchi, a Ph.D. student in the Datta Lab, who did the research for her dissertation. “Our work is a cross-pollination between the advances we have made at Sylvester and leading expertise nationally and globally. While our team has driven the work, the emphasis is always on team science.”

The research team leveraged cutting-edge technologies, including single cell biology, where they used spatial techniques to understand cellular relationships in the pancreatic tumor microenvironment. They used high-dimensional sequencing to understand the how cancer cells and neutrophils orchestrate this cross talk. They then brought it all together with mechanistic and translational studies using certain drugs to overcome chemotherapy resistance in cellular and animal models, as well as by using blood samples and tissue specimens accrued from actual patients at Sylvester.

“The whole point is this is extremely clinically actionable data,” Bianchi said.

The goal is to start clinical trials targeting this particular immunosuppressive pathway from multiple different angles, according to Dr. Datta.

“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 signaling mechanisms within neutrophils,” Dr. Datta said.

Being published in Cancer Discovery will help reach the goal, according to Bianchi.

Tags: Department of Microbiology and Immunology, Department of Public Health Sciences, Diabetes Research Institute, Dr. Jashodeep Datta, Dr. Nipun Merchant, Dr. Stephen Nimer, immature neutrophils, pancreatic cancer, Sylvester Comprehensive Cancer Center, Sylvester Pancreatic Cancer Research Institute, USNWR Oncology