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

Abstract

Somatic mutations are the most common oncogenic variants in lung cancer and are associated with poor prognosis. Using a-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 in patients with-mutant lung adenocarcinoma was an independent indicator of poor recurrence-free survival. We then showed that genetic ablation of 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. 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 SPCCCSP stem cells. Thus, we conclude that IL22 promotes -mutant lung tumorigenesis by driving a protumor inflammatory microenvironment with proliferative, angiogenic, and stemness contextual cues in epithelial/tumor cells..

IL22 drives cutaneous melanoma cell proliferation, migration and invasion through activation of miR-181/STAT3/AKT axis

“…edu/index.html; and The Human Protein Atlas, www.proteinatlas.org), however, both of these databases have no data about it. Since IL22 was found mainly produced by CD4 + T cells in tumor-bearing lung tissues, with a key role in modulation of pro-tumor inflammatory responses in lung cancer 20 , our results suggest the probability of IL22 expression being related to dysfunction of tumor-related CD4 + T cells in CM. Interestingly, as a previous study shown, naive tumor-specific CD4 + T cells could differentiate into cytotoxic T cells for melanoma clearance 31 , potentially supporting our opinion.…”

“…Previously, IL-22 expression was restricted to innate and adaptive immune cells, while the IL-22R seems to be confirmed in non-hematopoietic cells of the skin, lung, kidney and liver 27,28 . Recently study has revealed high expression levels of IL22 in both lung tumors and serum of patients with lung cancer, promoteing Kras mutant lung tumorigenesis 20 . Cutaneous melanoma is obviously different from ocular melanoma and mucosal melanoma in epidemiological features, clinical characteristics, treatment and outcomes 29,30 .…”

“…IL22 have been identified as an effecter secreted by CD4 + T cells that promotes lung tumorigenesis 20 . Recent studies found miR-181 with a clear effect on CD4 + T cell development and homeostasis, and involved in cellular apoptosis, differentiation and tumorigenesis 21,22 .…”

Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

“…In addition to IL-6, many reports in KRAS-driven lung tumor models have been associating mutant KRAS with protumoral cytokines, such as IL-8, IL-17, and IL-22 (Figure 2), which participate in the modulation of the immune microenvironment towards a pro-tumorigenic phenotype. Many of the effects orchestrated by these cytokines seem to be mediated by the transcription factor Signal transducer and activator of transcription 3 (STAT3) and most importantly, blocking these cytokines resulted in inhibition of tumor progression with concurrent re-education of the immune microenvironment [58][59][60][61][62][63]. In addition, in a KRASG12D-driven lung cancer model, the IL-6-STAT3 axis was shown to be essential for the cachexia phenotype, demonstrating the importance of targeting this pathway in advanced tumors [64].…”

Pin1 promotes pancreatic cancer progression and metastasis by activation of NF‐κB‐IL‐18 feedback loop

“…The activation of NF‐κB leads to cytokine production, especially IL‐6, IL‐11 and IL‐22, providing an inflammatory environment for the growth of premalignant tumours. Additionally, IL‐6 and IL‐11 activate STAT3 signalling, which works with NF‐κB to promote cancer development 4,33,34 . IL‐18, a pro‐inflammatory cytokine, was found to be downregulated by PPAR‐γ via inhibition of NF‐κB activity, thus influencing the expression of IL‐18‐induced adhesion molecules 35 .…”