The spleen contributes to the increase in PMN-MDSCs in orthotopic H22 hepatoma mice

Abstract

Myeloid-derived suppressor cells (MDSCs) are classified into polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs. The predominant subtype of MDSCs in hepatocellular carcinoma (HCC) is still elusive. The spleen is the largest immune organ in the body and is the origin of many cells. It is still unknown whether the spleen is the origin of MDSCs. In this study, we investigated the expression, origin and mobilization of the predominant MDSC subtype in H22 orthotopic hepatoma mice. Compared with M-MDSCs, PMN-MDSCs were increased and dominant in the spleen, peripheral blood and tumor tissues. Splenectomy could decrease the percentages of PMN-MDSCs in the peripheral blood and tumor tissues, increase the frequencies of NK cells in the peripheral blood and CD3⁺CD4⁺T, CD3⁺CD8⁺T, NK and NKT cells in the tumor tissues, reduce the tumor weight and the amounts of ascites, and prolong survival time in hepatoma mice. The levels of chemokine (CC motif) ligand 9 (CCL9) and chemokine (CC motif) ligand 2 (CCL2) were elevated in the peripheral blood of tumor-bearing (TB) mice, and their receptors CCR1 and CCR2 were expressed on spleen PMN-MDSCs. Migration assay showed that CCL2 and CCL9 could attract spleen PMN-MDSCs in vitro. These results indicate that PMN-MDSCs were increased and dominant in orthotopic H22 hepatoma mice, the spleen contributed to the increase of PMN-MDSCs, and PMN-MDSCs could be mobilized from the spleen to the peripheral blood by CCL9 and CCL2, thus facilitated tumor growth.

Keywords: CCL2; CCL9; Hepatoma; M-MDSCs; PMN-MDSCs; Spleen.