Excess Abdominal Fat Weakens Lung Immune Defenses, Raising Lung Cancer Risk, Roswell Park Study Finds

A team at Roswell Park Comprehensive Cancer Center in Buffalo has published findings in the Journal of Thoracic Oncology that point to excess abdominal fat as a driver of non-small cell lung cancer. The work argues that in people who are obese, the immune system's attack on developing tumors is weakened. That runs against earlier studies suggesting that people with a high body mass index were at lower risk of the disease.

The senior authors are Dr. Sai Yendamuri, Chair of Thoracic Surgery and a Senior Vice President and Chief Strategy Officer at Roswell Park, and Dr. Joseph Barbi, an Assistant Professor of Oncology in the Department of Immunology. Randall Smith Jr., PhD, of the Department of Thoracic Surgery, and Yeshwanth Vedire, MD, a former postdoctoral researcher at Roswell Park, are co-first authors.

The researchers focused on people already at elevated risk because of their smoking history. They analyzed data on 1,170 current or former smokers in an observational case-control study. One group had 576 people diagnosed with stage 1 or 2 non-small cell lung cancer who were treated with surgery at Roswell Park between 2009 and 2020. The comparison group had another 576 people who underwent lung cancer screening at Roswell Park between 2015 and 2022. Those in the screening group were followed for at least a year to see whether cancer developed later.

Both groups had CT scans that captured total fat area in the abdomen. The team describes this measure as more accurate and physiologically meaningful than BMI for defining overweight or obesity. Among the healthy but high-risk screening participants, those with relatively high total fat area were more likely than those with lower fat area to go on to develop lung cancer.

To understand why, the researchers examined the airway immune environment in human patients and in laboratory studies. The lungs of obese subjects contained higher numbers of regulatory T cells, or tregs, which appeared to play a key role in letting lung cancer grow unchecked. Other immune cells that would ordinarily be able to kill tumor cells appeared defective. In preclinical models, animals with excess fat developed lung tumors faster.

Dr. Yendamuri said the results provide strong evidence that obesity is a risk factor driving lung cancer development, and that strategies to correct obesity's effects on airway immune cells may help prevent or intercept early-stage lung cancers in high-risk people. Dr. Barbi said the work shows obesity impairs the lung's immune defenses before and during the early stages of tumor development.

The question has been unsettled for lung cancer in particular. Obesity has been shown to raise the risk of at least 13 types of cancer and to worsen outcomes after diagnosis, but its role in lung cancer has been less clear. The authors note the stakes: the share of the U.S. population with a BMI over 25 has climbed to 66% over the last 40 years, and more than half of that group falls into the obese category, with a BMI of 30 or higher.

The work was funded by several National Cancer Institute grants, including Roswell Park's Cancer Center Support Grant, along with money from the Roswell Park Alliance Foundation and the American Lung Association. The team is now working to identify other ways obesity compromises the lung's cancer-fighting immune defenses, and the mechanisms underneath them.