Oncotarget

Research Papers:

Interleukin-27 re-educates intratumoral myeloid cells and down-regulates stemness genes in non-small cell lung cancer

Irma Airoldi _, Maria Grazia Tupone, Silvia Esposito, Marco Vincenzo Russo, Giulia Barbarito, Giuseppe Cipollone and Emma Di Carlo

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Oncotarget. 2015; 6:3694-3708. https://doi.org/10.18632/oncotarget.2797

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Abstract

Irma Airoldi1,*, Maria Grazia Tupone2,3,*, Silvia Esposito2,3, Marco V. Russo2,3, Giulia Barbarito1, Giuseppe Cipollone4,5, Emma Di Carlo2,3

1Laboratory of Oncology, Istituto “Giannina Gaslini”, Genova 16147, Italy

2Anatomic Pathology and Molecular Medicine, Department of Medicine and Sciences of Aging, “G. d'Annunzio” University, Chieti 66100, Italy

3Ce.S.I. Biotech, Aging Research Center, “G. d'Annunzio” University Foundation, Chieti 66100, Italy

4Department of Experimental and Clinical Sciences, “G. d'Annunzio” University, Chieti 66100, Italy

5General and Thoracic Surgery, “SS Annunziata” Hospital, Chieti 66100, Italy

*These authors have contributed equally to this work

Correspondence to:

Emma Di Carlo, e-mail: edicarlo@unich.it

Keywords: cytokines, lung cancer, tumor microenvironment, inflammation, immunotherapy

Received: October 15, 2014     Accepted: November 20, 2014     Published: January 03, 2015

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.


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