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, Seyed Javad Moghaddam

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

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(7); 788-97. ©2018 AACR.

Original languageEnglish (US)
Pages (from-to)788-797
Number of pages10
JournalCancer Immunology Research
Volume6
Issue number7
DOIs
StatePublished - Jul 2018
Externally publishedYes

Keywords

  • Animals
  • Animals, Genetically Modified
  • Cell Transformation, Neoplastic/genetics
  • Disease Models, Animal
  • Gene Expression
  • Humans
  • Immunohistochemistry
  • Interleukins/genetics
  • Lung Neoplasms/etiology
  • Mice
  • Mutation
  • Neoplastic Stem Cells/immunology
  • Proto-Oncogene Proteins p21(ras)/genetics
  • STAT3 Transcription Factor/metabolism
  • Signal Transduction
  • Tumor Microenvironment

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