CD47-targeted immunotherapy unleashes antitumour immunity in Epstein-Barr virus-associated gastric cancer

The aims of this study were to enhance the antitumour immunity in Epstein-Barr virus-associated gastric cancer (EBVaGC). We performed RNA-seq analysis to compare the differential expression genes between EBVaGC and EBV-negative gastric cancer (EBVnGC) patients. The expression levels of CD68, CD163 and CD47 were analyzed by immunohistochemistry. Different subsets of macrophages were investigated by a coincubation model. The effects of CD47 blockade were also detected. The expression levels of CD68, CD163 and CD47 were significantly higher in EBVaGC, and were associated with poor prognoses. Macrophages coincubated with EBV+ AGS cells tended to be immunosuppressed, which could be reversed by CD47 deficiency or blocking CD47. EBV resulted in cGAS-STING pathway activation, which stimulated CD47 expression and inhibited macrophage phagocytosis. Anti-CD47 therapy activated cGAS-STING signaling, which was responsible for production of IFN-beta, resulting in activation of antitumour immunity. Our results provide a promising new strategy for CD47-targeted immunotherapy in EBVaGC.

Automated summary

The study aimed to enhance antitumour immunity in Epstein-Barr virus-associated gastric cancer (EBVaGC). RNA-seq analysis was performed to compare the differential expression genes between EBVaGC and EBV-negative gastric cancer (EBVnGC) patients. Immunohistochemistry was used to analyze the expression levels of CD68, CD163, and CD47. Different subsets of macrophages were investigated using a coincubation model. The study found that CD68, CD163, and CD47 were significantly upregulated in EBVaGC, and their expression levels were associated with poor prognoses. Macrophages coincubated with EBV+ AGS cells tended to be immunosuppressed, which could be reversed by CD47 deficiency or blocking CD47. EBV activated the cGAS-STING pathway, which stimulated CD47 expression and inhibited macrophage phagocytosis. Anti-CD47 therapy activated the cGAS-STING signaling, resulting in the production of IFN-beta and the activation of antitumour immunity. These findings provide a promising new strategy for CD47-targeted immunotherapy in EBVaGC.