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CD276 suppresses CAR-T cell function by promoting tumor cell glycolysis in esophageal squamous cell carcinoma
Guangxing Yue1, Jingwen Tang1, Lihan Zhang1
1Department of Integrated Chinese and Western Medicine, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
Background:
As an immune checkpoint that suppresses antitumor immunity, CD276 is a potential therapeutic target for cancer immunotherapy. However, the role of CD276 in esophageal squamous cell carcinoma (ESCC) has not been thoroughly examined. A greater understanding of the regulatory mechanism of CD276 may improve the clinical response and efficacy of cancer immunotherapy.
Methods:
The expression of CD276 was measured by qRT-PCR, IHC and flow cytometry analysis. T cell infiltration in ESCC was measured by qRT-PCR and immunofluorescence analysis. The regulation function of CD276 in glucose metabolism was examined by metabolism assays, western blotting and small molecule inhibitors. Transfection was used for gene editing. The oncogenic function of CD276 was examined in vivo by CAR-T cell therapy model.
Results:
Based on our findings, CD276 regulated the expression of the PKM2 gene in ESCC. Overexpression of CD276 induced the phosphorylation of PKM2 by the STAT3 signalling pathway to promote glucose metabolism in tumors. The accumulation of lactic acid in the tumor microenvironment has been reported to regulate the immune cells, particularly CD8+ T cells. We further analyzed the effect of CD276 on the function of T cells. Chimeric antigen receptor T cells (CAR-T) targeting human epidermal growth factor receptor 2 (HER2) were used as effector cells to detect the effect of CD276 on immunotherapy. The therapeutic effects of CAR-T cells were markedly limited by CD276 overexpression.
Conclusions:
Our results are the first to show that tumor-derived CD276 supports disease progression. Overexpression of CD276 promoted glucose metabolism in tumor and inhibited the function of CD8+ T cells. Therefore, strategies targeting CD276 might improve the response to cancer immunotherapy of ESCC patients.
Insights
CD276 overexpression in esophageal squamous cell carcinoma promotes tumor growth by increasing glucose metabolism and hindering CD8+ T cell function. Targeting CD276 may enhance cancer immunotherapy effectiveness.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- CD276 acts as an immune checkpoint, suppressing antitumor immunity and representing a potential target for cancer immunotherapy.
- The specific role of CD276 in esophageal squamous cell carcinoma (ESCC) and its regulatory mechanisms require further investigation to optimize immunotherapy outcomes.
Purpose of the Study:
- To investigate the role and regulatory mechanisms of CD276 in esophageal squamous cell carcinoma (ESCC).
- To determine the impact of CD276 on tumor glucose metabolism and T cell function.
- To evaluate the potential of targeting CD276 to improve cancer immunotherapy efficacy in ESCC.
Main Methods:
- CD276 expression analyzed using qRT-PCR, IHC, and flow cytometry.
- T cell infiltration assessed via qRT-PCR and immunofluorescence.
- CD276's role in glucose metabolism examined through metabolism assays, western blotting, and small molecule inhibitors.
- Gene editing performed using transfection; oncogenic function evaluated in vivo using a CAR-T cell therapy model.
Main Results:
- CD276 was found to regulate the pyruvate kinase M2 (PKM2) gene in ESCC.
- Overexpression of CD276 induced PKM2 phosphorylation via the STAT3 signaling pathway, enhancing tumor glucose metabolism.
- Tumor-derived CD276 overexpression impaired the therapeutic efficacy of chimeric antigen receptor T cells (CAR-T).
Conclusions:
- Tumor-derived CD276 promotes disease progression in ESCC by enhancing glucose metabolism and inhibiting CD8+ T cell function.
- CD276 overexpression limits the effectiveness of CAR-T cell immunotherapy.
- Targeting CD276 presents a promising strategy to improve immunotherapy response in ESCC patients.
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