title: IL6 Blockade Reprograms the Lung Tumor Microenvironment to Limit the Development and Progression of K-ras-Mutant Lung Cancer.
abstract: Activating mutations of K-ras are the most common oncogenic alterations found in lung cancer. Unfortunately, attempts to target K-ras-mutant lung tumors have thus far failed, clearly indicating the need for new approaches in patients with this molecular profile. We have previously shown NF-κB activation, release of IL6, and activation of its responsive transcription factor STAT3 in K-ras-mutant lung tumors, which was further amplified by the tumor-enhancing effect of chronic obstructive pulmonary disease (COPD)-type airway inflammation. These findings suggest an essential role for this inflammatory pathway in K-ras-mutant lung tumorigenesis and its enhancement by COPD. Therefore, here we blocked IL6 using a monoclonal anti-IL6 antibody in a K-ras-mutant mouse model of lung cancer in the absence or presence of COPD-type airway inflammation. IL6 blockade significantly inhibited lung cancer promotion, tumor cell-intrinsic STAT3 activation, tumor cell proliferation, and angiogenesis markers. Moreover, IL6 inhibition reduced expression of protumor type 2 molecules (arginase 1, Fizz 1, Mgl, and IDO), number of M2-type macrophages and granulocytic myeloid-derived suppressor cells, and protumor T-regulatory/Th17 cell responses. This was accompanied by increased expression of antitumor type 1 molecule (Nos2), and antitumor Th1/CD8 T-cell responses. Our study demonstrates that IL6 blockade not only has direct intrinsic inhibitory effect on tumor cells, but also reeducates the lung microenvironment toward an antitumor phenotype by altering the relative proportion between protumor and antitumor immune cells. This information introduces IL6 as a potential druggable target for prevention and treatment of K-ras-mutant lung tumors. Cancer Res; 76(11); 3189-99. ©2016 AACR.
authors.affiliation: Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mauricio S
authors.initials: MS
authors.lastname: Caetano
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Amber M
authors.initials: AM
authors.lastname: Cumpian
authors.affiliation: Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lei
authors.initials: L
authors.lastname: Gong
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Nese
authors.initials: N
authors.lastname: Unver
authors.affiliation: Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Ostrin
authors.affiliation: Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Soudabeh
authors.initials: S
authors.lastname: Daliri
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Chang
authors.affiliation: Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Cesar E
authors.initials: CE
authors.lastname: Ochoa
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Samir
authors.initials: S
authors.lastname: Hanash
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: Clinical Research Department, Brazilian Clinical Research Network (RNPCC), Rio de Janeiro, Brazil.
authors.forename: Cinthya
authors.initials: C
authors.lastname: Sternberg
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Humam
authors.initials: H
authors.lastname: Kadara
authors.affiliation: Clinical Research Department, Brazilian Clinical Research Network (RNPCC), Rio de Janeiro, Brazil.
authors.forename: Carlos Gil
authors.initials: CG
authors.lastname: Ferreira
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas Graduate School of Biomedical Sciences, Houston, Texas.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Watowich
authors.affiliation: Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas Graduate School of Biomedical Sciences, Houston, Texas. smoghadd@mdanderson.org.
authors.forename: Seyed Javad
authors.initials: SJ
authors.lastname: Moghaddam
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D063646:Carcinogenesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007124:Immunoenzyme Techniques; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009367:Neoplasm Staging; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects*; D000093242:Interleukin-6 Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D016328:NF-kappa B; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; C117307:KRAS protein, human