Abstract C034: Obesity-Linked Leptin Signaling Promotes Immune Checkpoint Expression and Tumor Cell Survival

Background: Obesity promotes cancer progression and immune evasion. B7-H3 (CD276), an immune checkpoint protein, is overexpressed in cancers and linked to tumor growth and therapy resistance. This study investigates whether leptin, an adipokine elevated in obesity, regulates B7-H3 expression and contributes to tumor progression and immune escape. Methods: HeLa and T47D cell lines were used to model tumor cells in the early phase of this study. Cells were treated with different concentrations of leptin to evaluate changes in B7-H3, phosphorylated STAT3 (pSTAT3), and PD-L1 expression. Quantitative real-time PCR (qRT-PCR) and Western blotting were employed to assess mRNA and protein expression, respectively. Leptin receptor (OBRb) knockdown was achieved using siRNA to investigate the involvement of leptin signaling. Apoptosis following OBRb knockdown was measured by flow cytometry using Annexin V/Propidium Iodide staining. Results: Leptin treatment led to significant upregulation of B7-H3, pSTAT3, and PD-L1 at both mRNA and protein levels. Silencing of OBRb reduced their expression and increased apoptotic cell populations, indicating a role for leptin in promoting tumor survival and immune evasion. Conclusion: These preliminary findings suggest leptin contributes to obesity-driven tumor progression via the B7-H3–pSTAT3–PD-L1 axis. Further in-depth studies are needed to validate these mechanisms and explore their potential as therapeutic targets in obesity-associated cancers. References: 1. Getu AA, Tigabu A, Zhou M, Lu J, Fodstad Ø, Tan M. New frontiers in immune checkpoint B7-H3 (CD276) research and drug development. Molecular Cancer. 2023 Mar 2;22(1):43. 2. Picarda E, Galbo Jr PM, Zong H, Rajan MR, Wallenius V, Zheng D, Börgeson E, Singh R, Pessin J, Zang X. The immune checkpoint B7-H3 (CD276) regulates adipocyte progenitor metabolism and obesity development. Science advances. 2022 Apr 27;8(17):eabm7012. Acknowledgements: This research is in part funded by China Medical University Ying-Tsai Scholar Fund CMU109-YT-04 (to M.T.) Citation Format: Iqra Kousar. Obesity-Linked Leptin Signaling Promotes Immune Checkpoint Expression and Tumor Cell Survival [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr C034.