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 journalArticle

10 Citations (Scopus)

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-kB pathway, along with induction of interleukin 6 (IL6) and an IL17-producing CD4 þ T-helper cell response. IL22 is an effector molecule secreted by CD4 þ and gd 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 þ 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 þ CCSP þ 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.

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

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Lung Neoplasms
Carcinogenesis
Epithelial Cells
T-Lymphocytes
Neoplasms
Lung
CD4 Antigens
NF-kappa B
Regulatory T-Lymphocytes
Immunosuppressive Agents
Helper-Inducer T-Lymphocytes
Cues
Interleukin-6
Pneumonia
Stem Cells
Cell Proliferation
Cytokines
Recurrence
Mutation
Survival

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

IL22 promotes kras-mutant lung cancer by induction of a protumor immune response and protection of stemness properties. / Khosravi, Nasim; Caetano, Mauricio S.; Cumpian, Amber M.; Unver, Nese; De la Garza Ramos, Cynthia; Noble, Oscar; Daliri, Soudabeh; Hernandez, Belinda J.; Gutierrez, Berenice A.; Evans, Scott E.; Hanash, Samir; Alekseev, Andrei M.; Yang, Yi; Chang, Seon Hee; Nurieva, Roza; Kadara, Humam; Chen, Jichao; Ostrin, Edwin J.; Moghaddam, Seyed Javad.

In: Cancer Immunology Research, Vol. 6, No. 7, 07.2018, p. 788-797.

Research output: Contribution to journalArticle

Khosravi, Nasim ; Caetano, Mauricio S. ; Cumpian, Amber M. ; Unver, Nese ; De la Garza Ramos, Cynthia ; Noble, Oscar ; Daliri, Soudabeh ; Hernandez, Belinda J. ; Gutierrez, Berenice A. ; Evans, Scott E. ; Hanash, Samir ; Alekseev, Andrei M. ; Yang, Yi ; Chang, Seon Hee ; Nurieva, Roza ; Kadara, Humam ; Chen, Jichao ; Ostrin, Edwin J. ; Moghaddam, Seyed Javad. / IL22 promotes kras-mutant lung cancer by induction of a protumor immune response and protection of stemness properties. In: Cancer Immunology Research. 2018 ; Vol. 6, No. 7. pp. 788-797.
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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-kB pathway, along with induction of interleukin 6 (IL6) and an IL17-producing CD4 {\th} T-helper cell response. IL22 is an effector molecule secreted by CD4 {\th} and gd 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 {\th} 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 {\th} CCSP {\th} 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.",
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T1 - IL22 promotes kras-mutant lung cancer by induction of a protumor immune response and protection of stemness properties

AU - Khosravi, Nasim

AU - Caetano, Mauricio S.

AU - Cumpian, Amber M.

AU - Unver, Nese

AU - De la Garza Ramos, Cynthia

AU - Noble, Oscar

AU - Daliri, Soudabeh

AU - Hernandez, Belinda J.

AU - Gutierrez, Berenice A.

AU - Evans, Scott E.

AU - Hanash, Samir

AU - Alekseev, Andrei M.

AU - Yang, Yi

AU - Chang, Seon Hee

AU - Nurieva, Roza

AU - Kadara, Humam

AU - Chen, Jichao

AU - Ostrin, Edwin J.

AU - Moghaddam, Seyed Javad

PY - 2018/7

Y1 - 2018/7

N2 - 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-kB pathway, along with induction of interleukin 6 (IL6) and an IL17-producing CD4 þ T-helper cell response. IL22 is an effector molecule secreted by CD4 þ and gd 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 þ 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 þ CCSP þ 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.

AB - 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-kB pathway, along with induction of interleukin 6 (IL6) and an IL17-producing CD4 þ T-helper cell response. IL22 is an effector molecule secreted by CD4 þ and gd 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 þ 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 þ CCSP þ 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.

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