Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor.
Tumor growth is associated with a profound alteration in myelopoiesis, leading to recruitment of immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs). We showed that among factors produced by various experimental tumors, the cytokines GM-CSF, G-CSF, and IL-6 allowed a rapid generation of MDSCs from precursors present in mouse and human bone marrow (BM). BM-MDSCs induced by GM-CSF+IL-6 possessed the highest tolerogenic activity, as revealed by the ability to impair the priming of CD8(+) T cells and allow long term acceptance of pancreatic islet allografts. Cytokines inducing MDSCs acted on a common molecular pathway and the immunoregulatory activity of both tumor-induced and BM-derived MDSCs was entirely dependent on the C/EBPbeta transcription factor. Adoptive transfer of tumor antigen-specific CD8(+) T lymphocytes resulted in therapy of established tumors only in mice lacking C/EBPbeta in the myeloid compartment, suggesting that C/EBPbeta is a critical regulator of the immunosuppressive environment created by growing cancers.
Marigo
Ilaria
I
Department of Oncology and Surgical Sciences, University of Padua, 35128 Padua, Italy.
Bosio
Erika
E
Solito
Samantha
S
Mesa
Circe
C
Fernandez
Audry
A
Dolcetti
Luigi
L
Ugel
Stefano
S
Sonda
Nada
N
Bicciato
Silvio
S
Falisi
Erika
E
Calabrese
Fiorella
F
Basso
Giuseppe
G
Zanovello
Paola
P
Cozzi
Emanuele
E
Mandruzzato
Susanna
S
Bronte
Vincenzo
V
D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000276:immunology*; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology*
D022782:CCAAT-Enhancer-Binding Protein-beta; D015850:Interleukin-6; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor