title: Interleukin-27 re-educates intratumoral myeloid cells and down-regulates stemness genes in non-small cell lung cancer.
abstract: Current therapies for Non-Small Cell Lung Cancer (NSCLC) still fail to significantly increase its survival rate. Here we asked whether Interleukin(IL)-27, which has revealed powerful antitumor activity and is toxicity-free in humans, is a promising therapeutic choice for NSCLC patients. IL-27's effects were tested on Adenocarcinoma (AC) and Squamous Cell Carcinoma (SCC) cell lines and xenograft models. IL-27Receptor(R) expression was assessed in lung tissues from 78 NSCLC patients. In vitro, IL-27 was ineffective on cancer cell proliferation or apoptosis, but fostered CXCL3/GROγ/MIP2β expression. In vitro and in vivo, IL-27 down-regulated stemness-related genes, namely SONIC HEDGEHOG in AC cells, and OCT4A, SOX2, NOTCH1, KLF4 along with Nestin, SNAI1/SNAIL, SNAI2/SLUG and ZEB1, in SCC cells. In vivo, IL-27 hampered both AC and SCC tumor growth in association with a prominent granulocyte- and macrophage-driven colliquative necrosis, CXCL3 production, and a reduced pluripotency- and EMT-related gene expression. Myeloablation of tumor-bearing hosts mostly abolished IL-27's antitumor effects. In clinical samples, IL-27R expression was found in AC, SCC, pre-cancerous lesions and tumor infiltrating myeloid cells, and correlated with advanced stages of disease. Our data suggest that even immunocompromised or advancer NSCLC patients may benefit from IL-27's antitumor properties based on its ability to drive myeloid cells towards antitumor activities, and down-regulate stemness- and EMT-related genes in cancer cells.
authors: Laboratory of Oncology, Istituto "Giannina Gaslini", Genova 16147, Italy.
authors: Irma
authors: I
authors: Airoldi
authors: Anatomic Pathology and Molecular Medicine, Department of Medicine and Sciences of Aging, "G. d'Annunzio" University, Chieti 66100, Italy.|Ce.S.I. Biotech, Aging Research Center, "G. d'Annunzio" University Foundation, Chieti 66100, Italy.
authors: Maria Grazia
authors: MG
authors: Tupone
authors: Anatomic Pathology and Molecular Medicine, Department of Medicine and Sciences of Aging, "G. d'Annunzio" University, Chieti 66100, Italy.|Ce.S.I. Biotech, Aging Research Center, "G. d'Annunzio" University Foundation, Chieti 66100, Italy.
authors: Silvia
authors: S
authors: Esposito
authors: Anatomic Pathology and Molecular Medicine, Department of Medicine and Sciences of Aging, "G. d'Annunzio" University, Chieti 66100, Italy.|Ce.S.I. Biotech, Aging Research Center, "G. d'Annunzio" University Foundation, Chieti 66100, Italy.
authors: Marco V
authors: MV
authors: Russo
authors: Laboratory of Oncology, Istituto "Giannina Gaslini", Genova 16147, Italy.
authors: Giulia
authors: G
authors: Barbarito
authors: Department of Experimental and Clinical Sciences, "G. d'Annunzio" University, Chieti 66100, Italy.|General and Thoracic Surgery, "SS Annunziata" Hospital, Chieti 66100, Italy.
authors: Giuseppe
authors: G
authors: Cipollone
authors: Anatomic Pathology and Molecular Medicine, Department of Medicine and Sciences of Aging, "G. d'Annunzio" University, Chieti 66100, Italy.|Ce.S.I. Biotech, Aging Research Center, "G. d'Annunzio" University Foundation, Chieti 66100, Italy.
authors: Emma
authors: E
authors: Di Carlo
mesh_terms: D000368:Aged; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D064094:Interleukin-27 / Q000494:pharmacology*; D000090062:Kruppel-Like Factor 4; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008875:Middle Aged; D022423:Myeloid Cells / Q000187:drug effects* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D064094:Interleukin-27; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D011994:Recombinant Proteins
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