Tumor-Induced Tolerance and Immune Suppression Depend on the C/EBPb Transcription Factor

Marigo, I. et. al. Immunity 32:790–802. (2010)

Speaker: Bernard Kiro (祁晨恩)                                   Time: 15:00~16:00, Sep 15, 2010

Commentator: Bei-Chang Yang Ph.D.(楊倍昌博士)   Place: Room 601

Abstract:

Tumors can induce a state of T cell unresponsiveness toward tumor antigens, i.e., tolerance, which subsequently evolves in a generalized failure to respond to various antigens, i.e., immune suppression, when the tumor progresses (1). Myeloid-derived suppressor cells (MDSCs) was first described as cell expressing CD11b and Gr-1 marker that can inhibit CD8⁺ T cell responses and its number increases in mice bearing tumor (2). Where dose MDSCs reside and how MDSCs differentiate is unclear. In this report it was determined that GM-CSF and IL-6 can induce bone marrow cells to differentiate into CD11b⁺Gr-1⁺ MDSCs with stronger T cell inhibitory ability than GM-CSF and G-CSF. By treating mice transplanted with allogeneic pancreatic islet with MDSCs derived from bone marrow induced with GM-CSF+IL-6 or GM-CSF+G-CSF or without MDSC treatment, survival rate of mice receiving MDSCs derived from GM-CSF+IL-6 induction has no significant difference to mice receiving syngeneic pancreatic islet transplantation. While C/EBPa is the master regulator of steady-state granulopoiesis, C/EBPb controls emergency granulopoiesis induced by cytokines and infections but it was never been associated with immune regulation. Bone marrow obtained from wild type mice and C/EBPb knock-out mice was incubated with GM-CSF+IL-6 to induce MDSCs, and as a result, C/EBPb knock-out mice had a impaired induction of MDSCs, and can’t inhibit CD8⁺ T cell response. In conclusion, C/EBPb is the key regulator for bone marrow cell to differentiate into MDSC and its ability to inhibit T cell activation.

References:

1.      Gabrilovich, D.I. et. al. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9:162–174. (2009)

2.      Bronte, V. et. al. Unopposed Production of Granulocyte-Macrophage Colony-Stimulating Factor by Tumors Inhibits CD8⁺ T Cell Responses by Dysregulating Antigen-Presenting Cell Maturation. J. Immunol. 162;5728–5737. (1999)