Sex-Specific Effects of Body Composition on Tumor Microenvironment in Non–Small Cell Lung Cancer

Abstract

BackgroundThere exists a gap in understanding the interaction between sex and obesity on tumor microenvironment in non–small cell lung cancer (NSCLC). We demonstrate the combined effects of sex and body composition on clinically relevant biomarkers of NSCLC immune response. MethodsA cohort of 409 patients with NSCLC was subdivided into 4 groups jointly defined by body mass index (BMI; cutoff of 25 kg/m2) and sex (male–high BMI, male–low BMI, female–high BMI, female–low BMI). Associations between these sex-BMI groups and tumor inflammation (expression of 161 immune response genes), cell proliferation (expression of 10 cell proliferation genes), and programmed cell death ligand 1 (PD-L1; through immunohistochemistry and targeted RNA sequencing) were assessed by Kruskal-Wallis and Wilcoxon rank sum tests for overall and pairwise tests, respectively. ResultsWe observed an overall significant association of sex-BMI with tumor inflammation (P < .001) and cell proliferation (P = .002). On pairwise analysis, high-BMI females had significantly higher tumor inflammation compared with low-BMI females (P = .002). In addition, women with a high (P = .004) and low (P = .008) BMI had significantly higher tumor inflammation compared with men with a high and low BMI, respectively. Low-BMI females (P = .01) and males (P = .01) had more cell proliferation. PD-L1 expression by RNA sequencing (P = .001) but not by immunohistochemical analysis differed significantly with sex-BMI. High-BMI females had significantly higher PD-L1 expression compared with low-BMI females (P = .01). ConclusionsWe demonstrate that tumor inflammation and PD-L1 expression are more strongly associated with BMI in women than in men. Additional studies are required to better understand the mechanisms underlying these effects and their role in response to checkpoint inhibitors in NSCLC.