Compositional Alterations in Immune Cells from Obese Mice Impair Anti-Tumor Cytotoxicity in Pancreatic Ductal Adenocarcinoma

Abstract

Background: Obesity is a major risk factor for pancreatic ductal adenocarcinoma (PDAC) and is associated with poor prognosis. Although metabolic and inflammatory disturbances linking obesity to PDAC progression are well-documented, the impact of obesity-induced immune dysfunction on the tumor microenvironment remains unclear.

Objective: This study aimed to elucidate the effects of obesity on the anti-tumor immune response in pancreatic cancer.

Design: Splenocytes isolated from mice fed a normal chow (NC) or high-fat diet (HFD) for 12 weeks were analyzed by flow cytometry. After co-culture with Panc02 cells, both splenocytes and PDAC cells (Panc02) were subjected to flow cytometry.

Results: Splenocytes derived from HFD-fed mice exhibited a markedly reduced abundance of CD8⁺ T and natural killer (NK) cells compared with those from NC-fed mice, despite unchanged cytokine-producing capacity. Co-culture experiments with Panc02 revealed that HFD-derived splenocytes significantly diminished tumor cell apoptosis, coinciding with reduced frequencies of CD8⁺ T and NK cells. Notably, while PD-1 expression on CD8⁺ T and NK cells remained stable, PD-L1 expression on Panc02 cells significantly decreased following co-culture with HFD-derived splenocytes.

Conclusions: These findings indicate that obesity impairs anti-tumor immunity in PDAC by reducing the abundance of cytotoxic lymphocytes, thereby limiting tumor cell apoptosis and PD-L1 induction.