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

Area of Science:

• Immunology
• Metabolic Reprogramming
• Cancer Biology

Background:

• Malignant neoplasms are a significant health concern.
• B7 homolog 3 (B7-H3 or CD276) is broadly expressed in tumors and influences glucose metabolism.
• The interplay between B7-H3-mediated metabolic changes and anti-tumor immune responses is not well understood.

Purpose of the Study:

• To investigate the association between B7-H3 expression and clinicopathological features in oral squamous cell carcinoma (OSCC).
• To elucidate the role of B7-H3 in glucose metabolism competition between OSCC cells and CD8+ T cells.
• To explore the impact of B7-H3 on CD8+ T cell function and the underlying molecular mechanisms.

Main Methods:

• Correlation analysis of B7-H3 expression with OSCC clinicopathological parameters.
• Co-culture experiments involving OSCC cells and flow cytometry-sorted CD8+ T cells.
• Measurement of glucose uptake, lactate secretion, and interferon-gamma (IFN-γ) release.
• Assessment of CD8+ T cell immune and exhaustion status.
• Investigation of the phosphoinositide3-kinase (PI3K)/Akt/mTOR signaling pathway.

Main Results:

• B7-H3 expression correlates with advanced OSCC stages, lymph node metastasis, and tumor location.
• B7-H3 enhances glycolysis in OSCC and melanoma cells while suppressing CD8+ T cell glycolysis.
• Silencing B7-H3 increases CD8+ T cell IFN-γ secretion and improves their anti-tumor function.
• Exogenous glucose supplementation can reverse the inhibitory effect of B7-H3 on T cell glycolysis.
• B7-H3's metabolic modulation of immune cells is potentially mediated via the PI3K/Akt/mTOR pathway.

Conclusions:

• B7-H3 plays a critical role in metabolic reprogramming within the tumor microenvironment, fostering tumorigenicity.
• Targeting B7-H3-driven metabolic alterations represents a promising strategy to enhance anti-tumor immunity.
• Understanding B7-H3's impact on glucose metabolism is key to developing novel cancer immunotherapies.