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

Yulu Wu1, Wenzhe Han1, Xiufa Tang1

  • 1State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.

Journal of Cancer
|April 5, 2024
PubMed

Insights

B7-H3 (CD276) promotes cancer growth by enhancing tumor cell glycolysis and inhibiting CD8+ T cell function in oral squamous cell carcinoma. Targeting this metabolic reprogramming offers a potential therapeutic strategy.

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.

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