C-type lectin receptor Dectin-1 blockade on tumour-associated macrophages improves anti-PD-1 efficacy in gastric cancer.

ABSTRACT

BACKGROUND: This study aimed to investigate the expression and clinical significance of Dendritic cell-associated C-type lectin-1 (Dectin-1) in gastric cancer (GC), and to explore the mechanism of Dectin-1 regulating tumour-associated macrophage (TAM)-mediated immune evasion in GC. METHODS: The association of Dectin-1+ cells with clinical outcomes was inspected by immunohistochemistry on tumour microarrays. Flow cytometry and RNA sequencing were applied to detect characteristics of T cells, phenotypic and transcriptional features of Dectin-1+ TAMs. The effect of Dectin-1 blockade was evaluated using an in vitro intervention experiment based on fresh GC tissues. RESULTS: High infiltration of intratumoral Dectin-1+ cells predicted poor prognosis in GC patients. Dectin-1+ cells were mainly composed of TAMs, and the accumulation of Dectin-1+ TAMs was associated with T-cell dysfunction. Notably, Dectin-1+ TAMs exhibited an immunosuppressive phenotype. Furthermore, blockade of Dectin-1 could reprogramme Dectin-1+ TAMs and reactivate anti-tumour effects of T cells, as well as enhanced PD-1 inhibitor-mediated cytotoxicity of CD8+ T cells against tumour cells. CONCLUSIONS: Dectin-1 could affect T-cell anti-tumour immune response by regulating the immunosuppressive function of TAMs, leading to poor prognosis and immune evasion in GC patients. Blockade of Dectin-1 can be used alone or in combination with current therapeutic strategies in GC.