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.
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.
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.