CD45CD33CD11b 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 CD45CD33CD11b MDSCs in the peripheral blood of GC patients compared to healthy individuals. CD45CD33CD11b MDSCs morphologically resembled neutrophils and expressed high levels of the neutrophil marker CD66b. Circulating CD45CD33CD11b 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 CD45CD33CD11b MDSCs also negatively correlated with the proportion of IFN-γCD8 T cell in the peripheral blood of GC patients. GC patient serum-derived IL-6 and IL-8 activated and induced CD45CD33CD11b 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 CD45CD33CD11b 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 CD45CD33CD11b MDSCs is functionally immunosuppressive and activated via the IL-6/IL-8-arginase I axis in GC patients.