Tumor remodeling pathways are enriched in the tumor microenvironment of obesity-associated colorectal cancer

Background: Obesity is a known risk factor for colorectal cancer (CRC) that promotes systemic inflammation and T-cell dysfunction, yet the characteristics of the tumor immune microenvironment (TIME) in obesity-associated CRC are not well-defined. Therefore, we performed a comprehensive analysis to characterize the unique immunological and genomic features of obesity-associated CRC. Methods: We performed genomic and transcriptomic analyses of patients with CRC stratified by body mass index (BMI) - obese (BMI ≥30), overweight (25≤ BMI <30), normal (18≤ BMI <25), and underweight (BMI<18). Data were obtained from the Oncology Research Information Exchange Network (ORIEN). Differential gene expression (DGE) and gene set enrichment analyses (GSEA) were performed to identify differentially expressed immune-related genes and altered biological pathways; immune deconvolution was performed to explore tumor immune microenvironment composition using CIBERSORT. Concurrently, genomic data were explored to compare the alteration frequency of selected genes ( APC, KRAS, TP53, SMAD4, PIK3CA, BRAF, NRAS, TGFBR2, MLH1, MSH2, MSH6, PMS2, CTNNB1, and PTEN ) using a Fisher's exact test. Statistical models were adjusted for covariates such as age, gender, and disease stage to isolate the effects of obesity. Results: Overall, 939 patients (obese: n=355; overweight: n=326; normal: n=242; underweight: n=16) were included. Male sex was more common as weight increases (p<0.0001) but disease stage was well balanced across BMI groups (p=0.581). GSEA revealed that obesity was significantly associated with pathways related to tissue remodeling, including epithelial-mesenchymal transition, coagulation, and angiogenesis. Conversely, normal weight status was characterized by the upregulation of metabolic processes such as oxidative phosphorylation and fatty acid metabolism, alongside pathways governing cell cycle progression and DNA repair (normalized enrichment score ≥ 2.0, adjusted p value <0.05). Although immune cell compositions via immune deconvolution did not differ between obese and normal weight groups, DGE analysis revealed higher expression of several immune checkpoint related genes such as CD276 (B7H3) and SIRPalpha (CD47 ligand) in the obesity group and CD73 (NT5E) and apoptosis-inducing gene, TNFSF10 (TRAIL) in the normal weight. The alteration frequency of selected genes was not significantly different between obese and normal groups. Conclusions: CRC with obesity is characterized by tumor remodeling whereas CRC without obesity had more upregulated metabolic processes in the TME. Differential expression status of key immune checkpoints between cases with and without obesity could indicate a tailored therapeutic target in this disease entity.