Critical role of myeloid-derived suppressor cells in tumor-induced liver immune suppression through inhibition of NKT cell function

Abstract

Metastasis followed by the tumor development is the primary cause of death for cancer patients. However, the underlying molecular mechanisms of how the growth of tumor resulted in the immune suppression, especially at the blood-enriched organ such as liver, were largely unknown. In this report, we studied the liver immune response of tumor-bearing (TB) mice using concanavalin A (Con A)-induced hepatitis model. We demonstrated that TB mice displayed an immune suppression phenotype, with attenuated alanine aminotransferase levels and liver damage upon Con A treatment. We also elucidated that large amounts of myeloid-derived suppressor cells (MDSCs) being influx into the liver in TB mice and these MDSCs were essential for liver immune suppression through both depletion and reconstitution approaches. We further determined that these MDSCs selectively suppressed the IFN-γ production deriving from NKT cells through membrane-bound transforming growth factor β (TGF-β). Finally, we defined a tumor-derived TGF-β-triggered CXCL1/2/5-and CXCR2-dependent recruitment of MDSC into the liver. In summary, our results defined a novel mechanism of liver immune suppression triggered by growing living tumor and provided possible therapeutic targets against these MDSCs.