Obesity Promotes Lung Carcinogenesis Through Airway Immune Dysfunction
Joseph Barbi1, Randall J Smith1, Yeshwanth R Vedire2
1Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
Summary
High abdominal fat area is linked to increased lung cancer risk and immune suppression. Obesity enhances lung carcinogenesis by upregulating immune suppressive mechanisms, challenging the obesity paradox theory.
Area of Science:
- Oncology
- Immunology
- Metabolic Disease
Background:
- Obesity is linked to immune dysfunction, yet paradoxically associated with decreased lung cancer risk.
- This phenomenon, known as the "Obesity Paradox," requires further investigation for mechanistic clarity.
Purpose of the Study:
- To investigate the relationship between obesity and lung cancer risk.
- To elucidate the underlying immunological mechanisms contributing to this association.
Main Methods:
- A case-control study analyzed lung cancer risk in relation to total abdominal fat area (TFA) using CT scans.
- Gene expression, immune cell profiling (flow cytometry), and preclinical models of lung carcinogenesis were employed.
- Analysis included airway gene expression, broncho-alveolar lavage, and murine lung immune contexture.
Main Results:
- Higher TFA was significantly associated with increased lung cancer risk in both univariate and multivariable analyses.
- Obesity was linked to suppressed immune activity in airways, characterized by increased regulatory T cells (Tregs) and myeloid cells.
- Preclinical models demonstrated that obesity exacerbates lung carcinogenesis, with obesity-enhanced Tregs promoting tumor growth and compromised immune surveillance.
Conclusions:
- Obesity is associated with enhanced lung carcinogenesis, contrary to the "Obesity Paradox".
- Immune suppression, driven by activated Tregs and other mechanisms, is upregulated in obesity and contributes to increased lung cancer risk.
- These findings highlight the detrimental role of obesity in lung cancer development and challenge existing paradigms.
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