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The prevalence of obesity, defined as the body mass index (BMI) ≥ 30 kg/m2, has reached epidemic levels. Obesity is associated with an increased risk of various cancers, including gastrointestinal ones. Recent evidence has suggested that obesity disproportionately impacts males and females with cancer, resulting in varied transcriptional and metabolic dysregulation. This study aimed to elucidate the differences in the metabolic milieu of adenocarcinomas of the gastrointestinal (GI) tract both related and unrelated to sex in obesity. To demonstrate these obesity and sex-related effects, we utilized three primary data sources: serum metabolomics from obese and non-obese patients assessed via the Biocrates MxP Quant 500 mass spectrometry-based kit, the ORIEN tumor RNA-sequencing data for all adenocarcinoma cases to assess the impacts of obesity, and publicly available TCGA transcriptional analysis to assess GI cancers and sex-related differences in GI cancers specifically. We applied and integrated our unique transcriptional metabolic pipeline in combination with our metabolomics data to reveal how obesity and sex can dictate differential metabolism in patients. Differentially expressed genes (DEG) analysis of ORIEN obese adenocarcinoma as compared to normal-weight adenocarcinoma patients resulted in large-scale transcriptional reprogramming (4029 DEGs, adj. p < 0.05 and |logFC| > 0.58). Gene Set Enrichment and metabolic pipeline analysis showed genes enriched for pathways relating to immunity (inflammation, and CD40 signaling, among others) and metabolism. Specifically, we found alterations to steroid metabolism and tryptophan/kynurenine metabolism in obese patients, both of which are highly associated with disease severity and immune cell dysfunction. These findings were further confirmed using the TCGA colorectal adenocarcinoma (CRC) and esophageal adenocarcinoma (ESCA) data, which showed similar patterns of increased tryptophan catabolism for kynurenine production in obese patients. These patients further showed disparate alterations between males and females when comparing obese to non-obese patient populations. Alterations to immune and metabolic pathways were validated in six patients (two obese and four normal weight) via CD8+/CD4+ peripheral blood mononuclear cell RNA-sequencing and paired serum metabolomics, which showed differential kynurenine and lipid metabolism, which corresponded with altered T-cell transcriptome in obese populations. Overall, obesity is associated with differential transcriptional and metabolic programs in various disease sites. Further, these alterations, such as kynurenine and tryptophan metabolism, which impact both metabolism and immune phenotype, vary with sex and obesity together. This study warrants further in-depth investigation into obesity and sex-related alterations in cancers that may better define biomarkers of response to immunotherapy.

Introduction: Preclinical evidence suggests that host obesity is associated with tumor progression due to immuno-metabolic dysfunction, but the impact of obesity on immunity and clinical outcomes in patients is poorly understood, with some studies suggesting an obesity paradox. We recently reported that high-adiposity and low-muscle body composition phenotypes are associated with striking increases in epithelial ovarian cancer (EOC) mortality and we observed no evidence of an obesity paradox. However, whether at-risk versus optimal body composition phenotypes are associated with distinct immuno-metabolic milieus remains a fundamental gap in knowledge. Herein, we defined differentially abundant circulating immuno-metabolic biomarkers according to body composition phenotypes in EOC. Methods: Muscle and adiposity cross-sectional area (cm2) was assessed using CT images from 200 EOC patients in The Body Composition and Epithelial Ovarian Cancer Survival Study at Roswell Park. Adiposity was dichotomized as low versus high; patients with skeletal muscle index (SMI) <38.5 (muscle cm2/height m2) were classified as low SMI (sarcopenia). Joint-exposure phenotypes were categorized as: Fit (normal SMI/low-adiposity), Overweight/Obese (normal SMI/high-adiposity), Sarcopenia/Obese (low SMI/high adiposity), and Sarcopenia/Cachexia (low SMI/low-adiposity). Treatment-naïve serum samples were assessed using Biocrates MxP Quant 500 for targeted metabolomics and commercially available Luminex kits for adipokines and Th1/Th2 cytokines. Limma moderated T-tests were used to identify differentially abundant metabolites and cytokines according to body composition phenotypes. Results: Patients with 'risk' phenotypes had significantly increased abundance of metabolites and cytokines that were unique according to body composition phenotype. Specifically, the metabolites and cytokines in increased abundance in the at-risk phenotypes are implicated in immune suppression and tumor progression. Conversely, increased abundance of lauric acid, IL-1β, and IL-2 in the Fit phenotype was observed, which have been previously implicated in tumor suppression and anti-tumor immunity. Conclusion: In this pilot study, we identified several significantly differentially abundant metabolites according to body composition phenotypes, confirming that clinically significant joint-exposure body composition phenotypes are also biologically distinct. Although we observed evidence that at-risk phenotypes were associated with increased abundance of immuno-metabolic biomarkers indicated in immune suppression, additional confirmatory studies focused on defining the link between body composition and immune cell composition and spatial relationships in the EOC tumor microenvironment are warranted. [ABSTRACT FROM AUTHOR]