Newswise — Pancreatic cysts have gained substantial attention in recent years because they represent one of the only precursors of pancreatic cancer identifiable through radiologic imaging. Although most of these cysts, also known as pancreatic intraductal papillary mucinous neoplasms (IPMNs), will remain benign, a subset of these neoplasms will progress to invasive cancer. While the immune system has been thought to play a role in the progression of IPMNs into pancreatic cancer, the specific mechanisms of its role has been unclear.

A UC San Francisco-led team of international researchers has outlined the comprehensive immune landscape and microbiome of pancreatic cysts as they progress from benign cysts to pancreatic cancer. Their findings, publishing August 31 in Lancet Gastroenterology and Hepatology, could reveal the mechanism of neoplastic progression and provide targets for immunotherapy to inhibit progression or treat invasive disease.

"This will have far reaching implications on how we think about utilizing immunotherapies to treat certain types of pancreatic cancer, and also potentially inhibit the formation and progression of cancer from pancreatic cysts," said senior author Ajay V. Maker, MD, FACS, FSSO, a pancreatic surgeon, chief of UCSF’s division of surgical oncology, and Maurice Galante Distinguished professor of surgical oncology.

The immune tumor microenvironment of the IPMNs evolves during malignant progression. A tumor microenvironment is the cellular environment that surrounds a tumor and includes immune cells and a stroma that supports other cells and tissues. A tumor and its microenvironment are constantly interacting with the microenvironment influencing both healthy and abnormal cell development (dysplasia).

As neoplasms progress from low-grade dysplasia to high-grade dysplasia and then to invasive carcinoma, a cytotoxic immune response rich in CD8+ T cells changes to an immunosuppressive environment with a measurable inflammatory response.

The researchers suggest that therapies that support cytotoxic T cells could be ideal for IPMNs with low-risk disease, whereas treatments that target regulatory T cells, myeloid-derived suppressor cells, and inhibitory macrophages could play a role in reducing malignant progression and treating high-risk disease. In addition to the treatment of IPMNs with an associated invasive carcinoma, addressing the immune tumor microenvironment could prevent the progression of IPMNs at high risk of malignant transformation.

The researchers discuss that with progressive amounts of dysplasia, the tumor microenvironment shows an increase in the concentration of pro-inflammatory and cyst fluid cytokines, which is indicative of a T-cell immunological response. The team’s research suggests that evaluation and characterization of the immune response to IPMNs could allow for early diagnosis, and potentially enhance treatments to halt progression or treat invasive disease.

The researchers also suggest that further studies addressing the tumor immune microenvironment of pre-invasive lesions are needed, including assessment of main-duct disease compared with branch-duct disease.

Authors: Additional authors include Tommaso Pollini, MD, of UCSF; Gabriele Capurso, MD, PhD, of IRCCS; Claudio Luchini, MD, PhD, Laura Maggino, MD, PhD, Giovanni Marchegiani, MD, PhD, Aldo Scarpa, MD, Claudio Bassi, MD, and Roberto Salvia, MD, PhD, of University of Verona; Volcan Adsay, MD, of Koc University; Marco Dal Molin, MD of University of Maryland Medical Center; Hanno Matthaei, MD, of University Hospital of Bonn; Irene Esposito, MD, PhD, of Heinrich Heine University; Ralph Hruban, MD, and Laura D Wood MD, PhD, of Johns Hopkins School of Medicine; Mari Mino-Kenudson, MD, of Harvard Medical School. The authors are members of the Verona Evidence-Based IPMN genetic alteration, microbiota, and microenvironment group.

Funding: Ajay V Maker’s research in tumor immunology is funded through the National Institutes of Health Method To Extend Research in Time award (R37CA238435), and he has the following pending or issued patents: WO2018183603A1 (PCT/US2018/025027) and US9757457B2. The paper contains additional funding information and disclosures.

About UCSF Health: UCSF Health is recognized worldwide for its innovative patient care, reflecting the latest medical knowledge, advanced technologies and pioneering research. It includes the flagship UCSF Medical Center, which is ranked among the top 10 hospitals nationwide, as well as UCSF Benioff Children’s Hospitals, with campuses in San Francisco and Oakland, Langley Porter Psychiatric Hospital and Clinics, UCSF Benioff Children’s Physicians and the UCSF Faculty Practice. These hospitals serve as the academic medical center of the University of California, San Francisco, which is world-renowned for its graduate-level health sciences education and biomedical research. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. Visit http://www.ucsfhealth.org/. Follow UCSF Health on Facebook or on Twitter.

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Journal Link: The Lancet Gastroenterology and Hepatology