Research in Brief: Why Some Sinus Polyps Keep Returning and How To Tackle Them

Scientists Uncover the “Cellular Conspiracy” Behind Chronic Sinus Disease

BOSTON — Chronic rhinosinusitis (CRS) is a surprisingly common but under-recognized disease that affects nearly one billion people worldwide, or about 12 percent of the population. Defined as a long-lasting inflammation of the nose and sinuses that lasts longer than 12 weeks, CRS is like having a bad cold and/or sinus infection that just won’t go away. Patients with CRS suffer from persistent nasal stuffiness and facial discomfort; more than a third of them develop stubborn nasal polyps that resist surgery and medication.

Now, scientists at Beth Israel Deaconess Medical Center (BIDMC), in close collaboration with colleagues at Stanford Medicine, have mapped the underlying biology driving this debilitating illness. Using leading-edge techniques, the team revealed for the first time how epithelial and immune cells interact to create a cycle of chronic inflammation. The findings, published in Immunity, open the door to new therapeutic approaches to CRS as well as other inflammatory conditions.

“The polyp patients are the ones who really suffer; they get these inflammatory masses that just keep coming back no matter what we do surgically,” said co-corresponding author Sizun Jiang, PhD, an assistant professor of medicine at BIDMC.

To better understand what drives polyps to develop in some patients, Jiang and colleagues in the lab of co-corresponding author Jayakar V. Nayak, MD, PhD, Professor of Otolaryngology – Head & Neck Surgery at Stanford Medicine, conducted one of the largest studies of its kind, analyzing tissue from more than 100 patients across North America and Asia. They used two powerful techniques: single-cell RNA sequencing, which shows what each individual cell is doing, and spatial transcriptomics, which reveals how those cells interact in their natural environment.

“This framework can be applied to other chronic inflammatory diseases,” said Jiang. “The patterns we identified aren’t unique to the nose: they’re fundamental principles of how tissues remodel in chronic inflammation. We’ve created a resource that other investigators can mine for years to come.”

About a third of people with CRS will develop nasal polyps, which are soft growths in the lining of the nasal passages filled with immune cells called eosinophils that normally help fight infection but, in CRS, make inflammation worse.

Jiang and colleagues revealed the intricate cellular crosstalk driving nasal polyp formation. “It’s like we found the cellular conspiracy behind the disease,” said lead author Guanrui Liao, MD, PhD, a former research fellow who performed the work while in the Jiang Lab at BIDMC.

The investigators showed that in patients with nasal polyps, the normal repair and defense systems of the nasal lining get hijacked. Immune cells called macrophages that normally fight infection switch roles and invite those tissue-damaging eosinophils into the affected tissues, while other cells that usually work to regenerate healthy tissue fuel polyp growth instead. Other immune players reinforce the loop, keeping the tissue inflamed and prone to polyp growth.

The team’s findings highlight specific points where therapies — existing ones and potentially others in the future — can intervene to break the cycle. Moreover, this study further showed a deeper mechanism of how a drug (Dupilumab) used to treat this disease works, by targeting the regenerative cells that go awry and fuel polyp growth instead.

Co-authors included Jason Yeung, Yao Yu Yeo, Yuzhou Chang, Dan H. Barouch, Maria Serena Longhi, and Vassiliki Boussiotis of BIDMC; Tsuguhisa Nakayama, Bokai Zhu, Ivan T. Lee, Axel Renteria, Dawn T. Bravo, David Zarabanda, Philip A. Gall, Sachi S. Dholakia, Nicole A. Borchard, Angela Yang, Dayoung Kim, Zara M. Patel, Peter H. Hwang, Michael T. Chang, Garry Nolan, Jayakar V. Nayak, Dhananjay Wagh, and John Coller of Stanford; Cankun Wang, Qin Ma, and Zihai Li of The Ohio State University; Steven Chun-Kang Liao, of National Taiwan University Hospital, Yunlin Branch; Dingani Nkosi of Brigham and Women’s Hospital; Jonathan B. Overdevest of Columbia University School of Medicine; Carol H. Yan of University of California, San Diego School of Medicine; Katie M. Phillipsof University of Cincinnati School of Medicine; Matt Lechner of University College London; Te-Huei Yeh of National Taiwan University Hospital, Hsin-Chu Branch.

This work was supported in part by the National Institutes of Health (grants DP2AI171139, P01AI177687, R01AI149672, U24CA224331, R01NS139479, R01HL151677, U54CA260517, U19AI171421, R01 HL16978701, and R01 HL15167704, R01GM152585, R01DK138504, P01CA278732, and U54AG075931); a Gilead’s Research Scholars Program in Hematologic Malignancies; a Sanofi iAward; the Broad Next Generation Award; the Dye Family Foundation; the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center; a CLIN-1 Award from CIRM; and the Pelotonia Institute of Immuno-Oncology.

Declaration of Interests: Jiang is a co-founder of Elucidate Bio Inc. and serves on its Board of Directors and Scientific Advisory Board and acknowledges research support from Sanofi and Roche unrelated to this work; Boussiotis has patents on the PD-1 pathway licensed by Bristol-Myers Squibb, Roche, Merck, EMD Serono, Boehringer Ingelheim, AstraZeneca, Novartis, and Dako unrelated to this work. For a complete list of disclosures, please see the publication.