B7-H3 suppresses CD8 + T cell immunologic function through reprogramming glycolytic metabolism

• Published in: Journal of Cancer Vol. 15; no. 9; pp. 2505 - 2517
• Main Authors: Wu, Yulu, Han, Wenzhe, Tang, Xiufa, Liu, Jiyuan, Guo, Zhiyong, Li, Zhangao, Cai, Chenchen, Que, Lin
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher 01-01-2024
• Subjects: Research Paper
• ISSN: 1837-9664; 1837-9664
• DOI: 10.7150/jca.90819

Malignant neoplasms pose a formidable threat to human well-being. Prior studies have documented the extensive expression of B7 homolog 3 (B7-H3 or CD276) across various tumors, affecting glucose metabolism. Yet, the link between metabolic modulation and immune responses remains largely unexplored. Our study reveals a significant association between B7-H3 expression and advanced tumor stages, lymph node metastasis, and tumor location in oral squamous cell carcinoma (OSCC). We further elucidate B7-H3's role in mediating glucose competition between cancer cells and CD8
T cells. Through co-culturing tumor cells with flow cytometry-sorted CD8
T cells, we measured glucose uptake and lactate secretion in both cell types. Additionally, we assessed interferon-gamma (IFN-γ) release and the immune and exhaustion status of CD8
T cells. Our findings indicate that B7-H3 enhances glycolysis in OSCC and malignant melanoma, while simultaneously inhibiting CD8
T cell glycolysis. Silencing B7-H3 led to increased IFN-γ secretion in co-cultures, highlighting its significant role in modulating CD8
T cell functions within the tumor microenvironment and its impact on tumorigenicity. We also demonstrate that glycolysis inhibition can be mitigated by exogenous glucose supplementation. Mechanistically, our study suggests B7-H3's influence on metabolism might be mediated through the phosphoinositide3-kinase (PI3K)/ protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) signaling pathway. This research unveils how B7-H3 affects immune functions via metabolic reprogramming.