CD45+CD33lowCD11bdim 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-gamma (IFN-gamma) and granzyme B (GrB) production. The proportion of CD45(+)CD33(low)CD11b(dim) MDSCs also negatively correlated with the proportion of IFN-gamma(+)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.