CD45 + CD33 low CD11b dim myeloid-derived suppressor cells suppress CD8 + T cell activity via the IL-6/IL-8-arginase I axis in human gastric cancer.

Myeloid-derived suppressor cells (MDSCs) are a prominent component of the pro-tumoral response. The phenotype of and mechanisms used by MDSCs is heterogeneous and requires more precise characterization in gastric cancer (GC) patients. Here, we have identified a novel subset of CD45 ⁺ CD33 ^low CD11b ^dim MDSCs in the peripheral blood of GC patients compared to healthy individuals. CD45 ⁺ CD33 ^low CD11b ^dim MDSCs morphologically resembled neutrophils and expressed high levels of the neutrophil marker CD66b. Circulating CD45 ⁺ CD33 ^low CD11b ^dim MDSCs effectively suppressed CD8 ⁺ T cells activity through the inhibition of CD8 ⁺ T cell proliferation and interferon-γ (IFN-γ) and granzyme B (GrB) production. The proportion of CD45 ⁺ CD33 ^low CD11b ^dim MDSCs also negatively correlated with the proportion of IFN-γ ⁺ CD8 ⁺ T cell in the peripheral blood of GC patients. GC patient serum-derived IL-6 and IL-8 activated and induced CD45 ⁺ CD33 ^low CD11b ^dim MDSCs to express arginase I via the PI3K-AKT signaling pathway. This pathway contributed to CD8 ⁺ T cell suppression as it was partially rescued by the blockade of the IL-6/IL-8-arginase I axis. Peripheral blood CD45 ⁺ CD33 ^low CD11b ^dim MDSCs, as well as IL-6, IL-8, and arginase I serum levels, positively correlated with GC progression and negatively correlated with overall patient survival. Altogether, our results highlight that a subset of neutrophilic CD45 ⁺ CD33 ^low CD11b ^dim MDSCs is functionally immunosuppressive and activated via the IL-6/IL-8-arginase I axis in GC patients.