CD45⁺CD33^lowCD11b^dim myeloid-derived suppressor cells suppress CD8⁺ T cell activity via the IL-6/IL-8-arginase I axis in human gastric cancer.

ABSTRACT: 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^lowCD11b^dim MDSCs in the peripheral blood of GC patients compared to healthy individuals. CD45⁺CD33^lowCD11b^dim MDSCs morphologically resembled neutrophils and expressed high levels of the neutrophil marker CD66b. Circulating CD45⁺CD33^lowCD11b^dim MDSCs effectively suppressed CD8⁺ T cells activity through the inhibition of CD8⁺ T cell proliferation and interferon-? (IFN-?) and granzyme B (GrB) production. The proportion of CD45⁺CD33^lowCD11b^dim MDSCs also negatively correlated with the proportion of IFN-?⁺CD8⁺ T cell in the peripheral blood of GC patients. GC patient serum-derived IL-6 and IL-8 activated and induced CD45⁺CD33^lowCD11b^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^lowCD11b^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^lowCD11b^dim MDSCs is functionally immunosuppressive and activated via the IL-6/IL-8-arginase I axis in GC patients.

SUBMITTER: Mao FY 

PROVIDER: S-EPMC6037756 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature