CD276 suppresses CAR-T cell function by promoting tumor cell glycolysis in esophageal squamous cell carcinoma

Abstract

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.

A new marker constructed from immune-related lncRNA pairs can be used to predict clinical treatment effects and prognosis: in-depth exploration of underlying mechanisms in HNSCC

“…CD276, a member of the B7 family, was considered a factor that regulated antigen-specific T cell immune response through costimulatory and co-inhibitory receptors. The expression of CD276 was negatively correlated with the number of tumor-infiltrating CD8 + T cells, and the upregulated expression was related to the poor prognosis in esophageal cancer [ 96 , 97 ]. In our study, patients in the high-risk group with more CD44 and CD276 expression exhibited a worse prognosis, which was consistent with the conclusions of these related studies.…”

Association between Metabolic Reprogramming and Immune Regulation in Digestive Tract Tumors

“…CD276, a potential therapeutic target for cancer immunotherapy, overexpressed in esophageal squamous cell carcinoma (ESCC) induces phosphorylation of PKM2 through the STAT3 signaling pathway to promote glucose metabolism in ESCC tumors and lactate accumulation in the TME. Additionally, it suppresses the function of CD8 + T cells while concurrently bolstering resistance to chimeric antigen receptor T-cell immunotherapy [34]. Therefore, CD276 may be a possible target for improving the effectiveness of ESCC immunotherapy.…”

CAR T cells redirected to B7-H3 for pediatric solid tumors: Current status and future perspectives

“…In non-small cell lung cancer, B7-H3 is associated with advanced stage and metastatic disease [ 77 , 78 ]. Across a range of gastrointestinal cancers including hepatocellular, gastric, pancreatic, esophageal, and colorectal, B7-H3 is expressed and often associated with poor prognosis [ 40 , 70 , 79 – 82 ]. In pancreatic cancer models, increased intensity of B7-H3 expression is seen in metastatic disease and associated with increased pathological stage [ 80 ].…”