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IL6 Blockade Reprograms the Lung Tumor Microenvironment to Limit the Development and Progression of K-ras-Mutant Lung Cancer
Cancer research (Chicago, Ill.), 2016-06, Vol.76 (11), p.3189-3199
Caetano, Mauricio S
Zhang, Huiyuan
Cumpian, Amber M
Gong, Lei
Unver, Nese
Ostrin, Edwin J
Daliri, Soudabeh
Chang, Seon Hee
Ochoa, Cesar E
Hanash, Samir
Behrens, Carmen
Wistuba, Ignacio I
Sternberg, Cinthya
Kadara, Humam
Ferreira, Carlos Gil
Watowich, Stephanie S
Moghaddam, Seyed Javad
2016
Details
Autor(en) / Beteiligte
Caetano, Mauricio S
Zhang, Huiyuan
Cumpian, Amber M
Gong, Lei
Unver, Nese
Ostrin, Edwin J
Daliri, Soudabeh
Chang, Seon Hee
Ochoa, Cesar E
Hanash, Samir
Behrens, Carmen
Wistuba, Ignacio I
Sternberg, Cinthya
Kadara, Humam
Ferreira, Carlos Gil
Watowich, Stephanie S
Moghaddam, Seyed Javad
Titel
IL6 Blockade Reprograms the Lung Tumor Microenvironment to Limit the Development and Progression of K-ras-Mutant Lung Cancer
Ist Teil von
Cancer research (Chicago, Ill.), 2016-06, Vol.76 (11), p.3189-3199
Ort / Verlag
United States
Erscheinungsjahr
2016
Link zum Volltext
Quelle
Free E-Journal (出版社公開部分のみ)
Beschreibungen/Notizen
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.
Sprache
Englisch
Identifikatoren
ISSN: 0008-5472
eISSN: 1538-7445
DOI: 10.1158/0008-5472.can-15-2840
Titel-ID: cdi_proquest_miscellaneous_1872828894
Format
–
Schlagworte
Adenocarcinoma - drug therapy
,
Adenocarcinoma - genetics
,
Adenocarcinoma - pathology
,
Animals
,
Antibodies, Monoclonal - pharmacology
,
Apoptosis
,
Blotting, Western
,
Carcinogenesis
,
Carcinoma, Non-Small-Cell Lung - drug therapy
,
Carcinoma, Non-Small-Cell Lung - genetics
,
Carcinoma, Non-Small-Cell Lung - pathology
,
Cell Proliferation
,
Disease Models, Animal
,
Disease Progression
,
Humans
,
Immunoenzyme Techniques
,
Interleukin-6 - antagonists & inhibitors
,
Interleukin-6 - genetics
,
Interleukin-6 - immunology
,
Interleukin-6 - metabolism
,
Lung Neoplasms - drug therapy
,
Lung Neoplasms - genetics
,
Lung Neoplasms - pathology
,
Mice
,
Mutation - genetics
,
Neoplasm Staging
,
NF-kappa B - genetics
,
NF-kappa B - metabolism
,
Prognosis
,
Proto-Oncogene Proteins p21(ras) - genetics
,
Pulmonary Disease, Chronic Obstructive - drug therapy
,
Pulmonary Disease, Chronic Obstructive - genetics
,
Pulmonary Disease, Chronic Obstructive - pathology
,
Real-Time Polymerase Chain Reaction
,
Reverse Transcriptase Polymerase Chain Reaction
,
RNA, Messenger - genetics
,
Signal Transduction
,
STAT3 Transcription Factor - genetics
,
STAT3 Transcription Factor - metabolism
,
Survival Rate
,
Tumor Cells, Cultured
,
Tumor Microenvironment - drug effects
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