Obesity Promotes Lung Carcinogenesis Through Airway Immune Dysfunction

Rationale: Despite clear links between obesity and dysfunctional anti-tumor immunity, a high Body Mass Index has been associated with decreased lung cancer risk, leading to an “Obesity Paradox”. Objective: We sought to clarify this relationship and gain mechanistic insights using both clinical and preclinical modeling. Methods & Measurements: 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 CT scans. Airway gene expression data from 278 additional patients was analyzed as a function of TFA, and obesity’s impact on chemical- and mutation-driven lung carcinogenesis models was examined. Effects on the immune contexture of murine lungs and patient broncho-alveolar lavage (n=109) were profiled using flow cytometry. Results: Lung cancer was linked to higher TFA in univariate and multivariable models. Gene expression in high-TFA airways suggested suppressed immune activity. Compared to 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, which was significantly exacerbated by obesity. Functional assays and depletion studies suggested obesity-enhanced Tregs can potentiate rapid tumor growth, and flow analysis of patients airway leukocytes further suggest compromised lung immune surveillance in patients of high TFA. Conclusions: Obesity is associated with enhanced lung carcinogenesis. Mechanisms of immune suppression upregulated with excess adiposity, including activated, functional Tregs, are evident in clinical and preclinical systems. These results refute the concept of an obesity paradox for lung cancer risk.