Delineation of monocytic and early-stage myeloid-derived suppressor cells in the peripheral blood of patients with hepatocarcinoma.

Abstract

In patients with hepatocellular carcinoma (HCC), increased myeloid-derived suppressor cells (MDSC) relate to aggressiveness and poor prognosis. Favorable responses with immune checkpoint inhibitors demonstrate that HCC is susceptible to immune activation, suggesting that the elimination of MDSC would provide therapeutic benefits. However, a global analysis of the different MDSC subsets in HCC is still missing. Here we phenotyped circulating myeloid cell subsets (monocytes, M-MDSC, PMN-MDSC and eMDSC) by flow cytometry in HCC and hepatocholangiocarcinoma patients and in healthy donors (HD). Isolated myeloid CD33⁺ cells were analyzed in immunosuppression assays, and cytokines were quantified in the supernatants. Arginase-1 activity (Arg-1) was analyzed in serum samples. All three proportions of MDSC, together with the immunosuppressive Arg-1, were significantly increased in HCC compared with HD. An important proportion of eMDSC expressed CD25, the IL-2 receptor α chain, and CD25⁺ eMDSC were also significantly expanded in HCC patients. HCC-CD33⁺ cells, enriched in M-MDSC and eMDSC, in vitro inhibited both CD4⁺ and CD8⁺ T cell proliferation and IL-2 production, and augmented IL-10, IL-6, and TNF-α. The correlation between the inhibition of T lymphocyte proliferation and M-MDSC was the strongest, while eMDSC or CD25⁺ eMDSC did not show antiproliferative capacity. Despite this functional difference, M-MDSC, CD25⁺ eMDSC, and CD25 expression in eMDSC were more prominent in advanced HCC as defined by a higher number of nodules, TNM stage, and alpha-fetoprotein level. This better delineation of M-MDSC and eMDSC phenotype and function in HCC could help to design therapies more likely to succeed in clinical trials.