Researchers Identify Potential Immune Evasion Mechanism in Premalignant Lung Lesions
Throughout a person’s lifetime, the cells lining the respiratory tract are exposed to inhaled pollutants, including cigarette smoke. These exposures can cause molecular changes that disrupt normal cell behavior, leading to abnormal growth and function. Over time, these airway abnormalities—called bronchial premalignant lesions—can progress to a type of non-small cell lung cancer known as squamous cell carcinoma.
In a new study from Boston University Chobanian & Avedisian School of Medicine, researchers have identified a microRNA (miRNA)—a small non-coding RNA that can suppress gene expression—that is overexpressed in lesions that progress in severity. This miRNA reduces the expression of genes involved in immune recognition, potentially enabling abnormal cells to evade detection by the immune system.
They also found that miRNA expression was highest in severe lesions, particularly those that later progressed. High miRNA expression was also associated with lower expression of immune recognition genes, and lesions with elevated miRNA levels showed fewer immune cells in close spatial proximity to the abnormal cells. Together, these findings suggest a mechanism that may promote progression to cancer and highlight a potential therapeutic pathway to target for lung cancer prevention.
Jennifer Beane, PhD“By studying how these lesions change over time in patients at high risk for lung cancer due to age and smoking history, we can begin to understand why some lesions worsen and progress toward cancer while others remain stable or regress. If we can reliably identify and treat the lesions most likely to progress and treat them before invasion occurs, we may be able to reduce lung cancer mortality,” explained corresponding author Jennifer Beane, PhD, associate professor of medicine at the school.
Biopsies of bronchial premalignant lesions were collected from patients using bronchoscopy at Roswell Park Comprehensive Cancer Center in Buffalo, NY. RNA was isolated from each biopsy and profiled using RNA sequencing and miRNA sequencing, which quantify gene and miRNA expression in the tissue sample. In total, the researchers analyzed 167 biopsies from 30 patients. Using computational analyses, they identified a miRNA—miR-149-5p—that was associated with reduced expression of NLRC5, a regulator of genes involved in immune recognition of abnormal cells. To validate these findings, they performed spatial analyses on biopsy tissue to localize airway cell types and to quantify miR-149-5p and its downstream protein targets. These experiments confirmed that miR-149-5p was more abundant and NLRC5 was less abundant in airway epithelial cells from more severe, progressive lesions, and that fewer immune cells were in close proximity to these cells.
The researchers hope this study will help enable new strategies to intercept lung cancer before it develops. “More broadly, as exposure to inhaled environmental pollutants continues to rise, a detailed understanding of how the respiratory tract responds to—and can potentially recover from—these insults is needed to identify effective ways to prevent or reverse cellular damage,” adds Beane.
These findings appear online in the journal Cancer Immunology Research.
This work was supported by grants from the National Institutes of Health that include National Cancer Institute R21-CA253498, National Cancer Institute U2C-CA233238, National Cancer Institute U2C-CA271898, National Center for Advancing Translational Sciences through BU- 875 CTSI Grant Number 1UL1TR001430, National Heart, Lung, and Blood Institute R01-HL124392. This work was also supported by sponsored research grants from Johnson and Johnson, the LUNGevity Foundation, the American Lung Association, and a CDMRP Lung Cancer Research Program Idea Development Award LC230511.