RORC1 Regulates Tumor-Promoting "Emergency" Granulo-Monocytopoiesis.
Cancer-driven granulo-monocytopoiesis stimulates expansion of tumor promoting myeloid populations, mostly myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). We identified subsets of MDSCs and TAMs based on the expression of retinoic-acid-related orphan receptor (RORC1/RORγ) in human and mouse tumor bearers. RORC1 orchestrates myelopoiesis by suppressing negative (Socs3 and Bcl3) and promoting positive (C/EBPβ) regulators of granulopoiesis, as well as the key transcriptional mediators of myeloid progenitor commitment and differentiation to the monocytic/macrophage lineage (IRF8 and PU.1). RORC1 supported tumor-promoting innate immunity by protecting MDSCs from apoptosis, mediating TAM differentiation and M2 polarization, and limiting tumor infiltration by mature neutrophils. Accordingly, ablation of RORC1 in the hematopoietic compartment prevented cancer-driven myelopoiesis, resulting in inhibition of tumor growth and metastasis.
Department of Inflammation and Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy.
Laura
L
Strauss
Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.
Sabina
S
Sangaletti
Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro," Via Bovio 6, 28100 Novara, Italy.
Francesca Maria
FM
Consonni
Department of Inflammation and Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy.
Gabor
G
Szebeni
Department of Inflammation and Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy.
Sara
S
Morlacchi
Department of Inflammation and Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy.
Maria Grazia
MG
Totaro
Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro," Via Bovio 6, 28100 Novara, Italy.
Chiara
C
Porta
Department of Inflammation and Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy.
Achille
A
Anselmo
Department of Inflammation and Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy.
Silvia
S
Tartari
Department of Inflammation and Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy.
Andrea
A
Doni
Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro," Via Bovio 6, 28100 Novara, Italy.
Francesco
F
Zitelli
Tumor Immunology Unit, Department of Health Sciences, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy.
Claudio
C
Tripodo
Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.
Mario P
MP
Colombo
Department of Inflammation and Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy; Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro," Via Bovio 6, 28100 Novara, Italy. Electronic address: antonio.sica@humanitasresearch.it.
Antonio
A
Sica
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006098:Granulocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D038042:Myelopoiesis / Q000235:genetics*; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000235:genetics
D016207:Cytokines; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3