Obesity Promotes Lung Carcinogenesis Through Airway Immune Dysfunction

Despite clear links between obesity and dysfunctional antitumor immunity, a high body mass index has been associated with decreased lung cancer risk, leading to an "obesity paradox." We sought to clarify this relationship and gain mechanistic insights using both clinical and preclinical modeling.

A case-control study of early stage lung cancer risk was conducted in 1170 high-risk individuals (594 with cancer) stratified by total abdominal fat area (TFA) determined using computed tomography scans. Airway gene expression data from 278 additional patients were analyzed as a function of TFA, and obesity's impact on chemical- and mutation-driven lung carcinogenesis models was evaluated. Effects on the immune contexture of murine lungs and patient broncho-alveolar lavage (n = 109) were profiled using flow cytometry.

Lung cancer was linked to higher TFA in univariate and multivariable models. Gene expression in high-TFA airways suggested suppressed immune activity. Compared with lean controls, the lungs of obese mice displayed abundant potentially suppressive myeloid cells, activated regulatory T cells, and effector T cell deficits at baseline and during carcinogenesis, a process significantly exacerbated by obesity. Functional assays and depletion studies suggested that obesity-enhanced regulatory T cells can potentiate rapid tumor growth, and flow analysis of patient airway leukocytes further suggests compromised lung immune surveillance in patients with high TFA.

Obesity is associated with enhanced lung carcinogenesis. Mechanisms of immune suppression up-regulated with excess adiposity, including activated, functional regulatory T cells, are evident in clinical and preclinical systems. These results challenge the concept of an obesity paradox regarding lung cancer risk.