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Research Article

IL22 Promotes Kras-Mutant Lung Cancer by Induction of a Protumor Immune Response and Protection of Stemness Properties

Nasim Khosravi, Mauricio S. Caetano, Amber M. Cumpian, Nese Unver, Cynthia De la Garza Ramos, Oscar Noble, Soudabeh Daliri, Belinda J. Hernandez, Berenice A. Gutierrez, Scott E. Evans, Samir Hanash, Andrei M. Alekseev, Yi Yang, Seon Hee Chang, Roza Nurieva, Humam Kadara, Jichao Chen, Edwin J. Ostrin and Seyed Javad Moghaddam
Nasim Khosravi
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Mauricio S. Caetano
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Amber M. Cumpian
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Nese Unver
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Cynthia De la Garza Ramos
Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo León, México.
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Oscar Noble
Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo León, México.
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Soudabeh Daliri
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Belinda J. Hernandez
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Berenice A. Gutierrez
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Scott E. Evans
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Samir Hanash
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Andrei M. Alekseev
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Yi Yang
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.Department of Radiation Oncology, The Second Hospital of Jilin University, China.
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Seon Hee Chang
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Roza Nurieva
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas.
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Humam Kadara
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
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Jichao Chen
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas.
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Edwin J. Ostrin
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Seyed Javad Moghaddam
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas.
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  • For correspondence: smoghadd@mdanderson.org
DOI: 10.1158/2326-6066.CIR-17-0655
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Abstract

Somatic KRAS mutations are the most common oncogenic variants in lung cancer and are associated with poor prognosis. Using a Kras-induced lung cancer mouse model, CC-LR, we previously showed a role for inflammation in lung tumorigenesis through activation of the NF-κB pathway, along with induction of interleukin 6 (IL6) and an IL17-producing CD4+ T-helper cell response. IL22 is an effector molecule secreted by CD4+ and γδ T cells that we previously found to be expressed in CC-LR mice. IL22 mostly signals through the STAT3 pathway and is thought to act exclusively on nonhematopoietic cells with basal IL22 receptor (IL22R) expression on epithelial cells. Here, we found that higher expression of IL22R1 in patients with KRAS-mutant lung adenocarcinoma was an independent indicator of poor recurrence-free survival. We then showed that genetic ablation of Il22 in CC-LR mice (CC-LR/IL22KO mice) caused a significant reduction in tumor number and size. This was accompanied by significantly lower tumor cell proliferation, angiogenesis, and STAT3 activation. Il22 ablation was also associated with significant reduction in lung-infiltrating inflammatory cells and expression of protumor inflammatory cytokines. Conversely, this was accompanied with increased antitumor Th1 and cytotoxic CD8+ T-cell responses, while suppressing the protumor immunosuppressive T regulatory cell response. In CC-LR/IL22KO mice, we found significantly reduced expression of core stemness genes and the number of prototypical SPC+CCSP+ stem cells. Thus, we conclude that IL22 promotes Kras-mutant lung tumorigenesis by driving a protumor inflammatory microenvironment with proliferative, angiogenic, and stemness contextual cues in epithelial/tumor cells. Cancer Immunol Res; 6(8); 1–10. ©2018 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Received November 14, 2017.
  • Revision received March 22, 2018.
  • Accepted May 9, 2018.
  • Published first May 15, 2018.
  • ©2018 American Association for Cancer Research.

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Published OnlineFirst June 7, 2018
doi: 10.1158/2326-6066.CIR-17-0655

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IL22 Promotes Kras-Mutant Lung Cancer by Induction of a Protumor Immune Response and Protection of Stemness Properties
Nasim Khosravi, Mauricio S. Caetano, Amber M. Cumpian, Nese Unver, Cynthia De la Garza Ramos, Oscar Noble, Soudabeh Daliri, Belinda J. Hernandez, Berenice A. Gutierrez, Scott E. Evans, Samir Hanash, Andrei M. Alekseev, Yi Yang, Seon Hee Chang, Roza Nurieva, Humam Kadara, Jichao Chen, Edwin J. Ostrin and Seyed Javad Moghaddam
Cancer Immunol Res June 7 2018 DOI: 10.1158/2326-6066.CIR-17-0655

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IL22 Promotes Kras-Mutant Lung Cancer by Induction of a Protumor Immune Response and Protection of Stemness Properties
Nasim Khosravi, Mauricio S. Caetano, Amber M. Cumpian, Nese Unver, Cynthia De la Garza Ramos, Oscar Noble, Soudabeh Daliri, Belinda J. Hernandez, Berenice A. Gutierrez, Scott E. Evans, Samir Hanash, Andrei M. Alekseev, Yi Yang, Seon Hee Chang, Roza Nurieva, Humam Kadara, Jichao Chen, Edwin J. Ostrin and Seyed Javad Moghaddam
Cancer Immunol Res June 7 2018 DOI: 10.1158/2326-6066.CIR-17-0655
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