Tumor conditions induce bone marrow expansion of granulocytic, but not monocytic, immunosuppressive leukocytes with increased CXCR2 expression in mice. Issue 3 (8th December 2017)

• Record Type: Journal Article
• Authors: Bian, Zhen; Shi, Lei; Venkataramani, Mahathi; Abdelaal, Ahmed Mansour; Culpepper, Courtney; Kidder, Koby; Liang, Hongwei; Zen, Ke; Liu, Yuan
• Is Part Of: European journal of immunology. Volume 48:Issue 3(2018)
• Page Start: 532
• Page End: 542
• Publication Date: 2017-12-08
• Subjects: Bone marrow PMN -- Ly6C -- Melanoma -- Myeloid‐derived suppressor cells -- Myelopoiesis; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201746976
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: Myeloid‐derived suppressor cells (MDSCs) promote tumor growth through, in part, inhibiting T‐cell immunity. However, mechanisms underlying MDSC expansion and guidance of MDSCs toward the tumor microenvironment remain unclear. Employing Percoll density gradients, we separate bone marrow (BM) leukocytes from tumor‐bearing mice into four density‐increasing bands with myeloid leukocytes enriched in bands III and IV. Band III comprises monocytes and low‐density granulocytes, both confirmed to be M‐MDSCs and G‐MDSCs, respectively, by displaying potent inhibition of T‐cell proliferation. However, monocytes act as M‐MDSCs not only under tumor conditions but also the healthy condition. In contrast, band IV contains non‐inhibitory, mature granulocytes. Only band III G‐MDSCs display significant expansion in mice bearing B16 melanoma, Lewis lung carcinoma, or MC38 colon carcinoma. The expanded G‐MDSCs also show increased CXCR2 expression, which guides egress out of BM, and produce arginase‐1 and ROS upon encountering antigen‐activated T cells. Adoptive transfer assays demonstrate that both G‐MDSCs and mature granulocytes infiltrate tumors, but only the former displays sustention and accumulation. Intratumoral administrations of granulocytes further demonstrate that G‐MDSCs promote tumor growth, whereas mature granulocytes exert minimal effects, or execute powerful anti‐tumor effects providing the presence of PMN activation mechanisms in the tumor microenvironment. Abstract : The tumor condition alters bone marrow myelopoiesis, significantly expanding low‐density G‐MDSCs and upregulating CXCR2 expression. Both G‐MDSCs and PMN demonstrate tumor‐infiltrating capacity, but only the former promote cancer development. PMN, however, execute anti‐tumor effects providing the presence of activation mechanisms. Moreover, monocytes are constitutive M‐MDSCs even under healthy conditions.