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Published on: November 28, 2019
Lactate-induced metabolic reprogramming of TAMs impairs antigen presentation capacity via C/EBPα-CD74 axis in oral
Mengyao Wang1,2,3, Mengqi Wang1,2,3, Zizhen Gong1,2,3
1Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.
Background:
Throughout oral squamous cell carcinoma (OSCC) progression, tumor-associated macrophages (TAMs) lose their antigen-presenting capacity and anti-tumor function. The mechanisms that cause this dysfunction are not fully understood. CD74 is essential for antigen-presenting process, while little direct evidence describes its role in TAMs' immune function.
Methods:
We integrated single-cell transcriptomic analysis, clinical cohort validation and CD74 conditional knockout mouse model to investigate the role of CD74 in TAMs during OSCC progression. Metabolomic analysis and mechanistic studies were performed to dissect how lactate-mediated metabolic reprogramming regulates CD74 expression.
Results:
We demonstrate that lactate accumulation in TME induces metabolic reprogramming of TAMs, which drives the acetylation of C/EBPα, and consequently suppresses CD74 expression. This downregulation of CD74 impairs the antigen-presenting capacity of TAMs, suppresses T cell activation, and ultimately promotes OSCC progression and recurrence.
Conclusions:
Our findings reveal the critical role of the lactate-C/EBPα-CD74 axis in shaping TAMs function, and provide potential therapeutic target for OSCC immunotherapy.
Key Points:
CD74hi TAMs decrease during OSCCprogression and are associated with patient prognosis. Loss of CD74 impairs antigen presentation andsuppresses T cell activation. Tumor-derived lactateinhibits CD74 transcription via C/EBPα acetylation.
Insights
Lactate accumulation in oral tumors suppresses CD74 expression in macrophages, impairing their anti-tumor function and promoting cancer progression. This highlights a key pathway for oral squamous cell carcinoma (OSCC) immunotherapy.
Area of Science:
- Immunology
- Oncology
- Cancer Metabolism
Background:
- Tumor-associated macrophages (TAMs) in oral squamous cell carcinoma (OSCC) lose anti-tumor functions during disease progression.
- The precise mechanisms behind TAM dysfunction in OSCC remain unclear.
- CD74 is crucial for antigen presentation, but its specific role in TAM immune function is under-investigated.
Purpose of the Study:
- To elucidate the role of CD74 in TAMs during OSCC progression.
- To investigate the mechanisms by which lactate influences CD74 expression and TAM function in the tumor microenvironment (TME).
Main Methods:
- Integrated single-cell transcriptomic analysis.
- Clinical cohort validation.
- CD74 conditional knockout mouse models.
- Metabolomic analysis and mechanistic studies.
Main Results:
- Lactate accumulation in the TME reprograms TAM metabolism, leading to C/EBPα acetylation and suppressed CD74 expression.
- Downregulation of CD74 impairs TAM antigen-presenting capacity and suppresses T cell activation.
- Reduced CD74 expression in TAMs correlates with OSCC progression and poorer patient prognosis.
Conclusions:
- The lactate-C/EBPα-CD74 axis critically regulates TAM function in OSCC.
- Targeting this axis offers a potential therapeutic strategy for OSCC immunotherapy.
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