IL-9 Exerts Antitumor Effects in Colon Cancer and Transforms the Tumor Microenvironment <i>In Vivo</i>

Wang, Jin; Sun, Mingbing; Zhao, Hua; Huang, Yang; Li, Dongbao; Mao, Deli; Zhang, Zhe; Zhu, Xinguo; Dong, Xiaoqiang; Zhao, Xin

doi:10.1177/1533033819857737

Cited by 31 publications

(30 citation statements)

References 46 publications

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“…However, in line with our results, high levels of IL-2 in CRC patients was observed 430 also by Bosek et al 104 . Regarding IL-9, contrary to our result, Wang et al shown that IL -9 was less 431 expressed in human colon carcinoma 105 . However, even Huang et al reported low amounts of IL-9 432 in tissue and plasma of CRC patients but these low levels were associated with tumor progression 106 .…”

Section: Statistical Analysis Of the Association Between Tissue Microcontrasting

confidence: 99%

Significant and conflicting correlation of IL-9 withPrevotellaandBacteroidesin human colorectal cancer

Niccolai

Russo

Baldi

et al. 2020

Preprint

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20Background: Colorectal cancer (CRC) is a widespread disease that represents an example of chronic 21 inflammation-associated tumor. In fact, the immune system, besides protecting the host from 22Aim: The cellular and molecular characterization of the immune response and the evaluation of GM 33 composition in healthy and tumor mucosa, focusing on the correlation between cytokines' profile and 34 GM signature. 35 36 Methods: We collected tumoral (CRC) and healthy (CRC-S) mucosa samples of 45 CRC patients. 37 For each sample, we characterized the Tissue Infiltrating Lymphocytes (TIL)'s subset profile and the 38 GM composition. In addition, in 14 CRC patients, we evaluated the CRC and CRC-S molecular 39 inflammatory response (26 cytokines/chemokines) and we correlated this profile with GM 40 composition using the Dirichlet Multinomial Regression. 41 42Results: The analysis of T cells subsets distribution showed that CRC samples displayed higher 43 percentages of Th17, Th2, Tregs, Tc17, Tc1/Tc17, and Tcreg, compared to CRC-S. Notably, also the 44 number of Th9 was higher, even if not significantly, in CRC tissue compared to healthy one. In 45 addition, we found that MIP-1α, IL-1β, IL-2, IP-10, IL-6, IL-8, IL-17A, IFN-γ, TNF-α, MCP-1, IL-46 1α, P-selectin and IL-9 were significantly increased in CRC compared to CRC-S. Moreover, the GM 47 analysis revealed that CRC samples had significantly higher levels of Fusobacteria, Proteobacteria, 48Fusobacterium, Ruminococcus2 (Lachnospiraceae family) and Ruminococcus (Ruminococcaceae 49 family) than CRC-S. Finally, we found that the abundance of Prevotella spp in CRC samples was 50 negatively correlated with IL-17A and positively with IL-9. In addition, the abundance of Bacteroides 51and Escherichia/Shigella species in CRC samples showed a negative association with IL-9 and IP-10 52 respectively. 53 54 Conclusions: Our data show a clear dissimilarity of inflammatory profile and GM composition 55 between the tumor and the adjacent healthy tissue, displaying the generation of a peculiar CRC 56 microenvironment. Interestingly, relating the tissue cytokine profile with the GM composition, we 57 confirmed the presence of a bidirectional crosstalk between the immune response and the host's 58 commensal microorganisms; in detail, we documented for the first time that Prevotella spp. and 59 Bacteroides spp. are correlated (positively and negatively, respectively) with the IL-9, whose role in 60 CRC development is still debated. 61 62 63

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Section: Statistical Analysis Of the Association Between Tissue Microcontrasting

confidence: 99%

Significant and conflicting correlation of IL-9 withPrevotellaandBacteroidesin human colorectal cancer

Niccolai

Russo

Baldi

et al. 2020

Preprint

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“…However, no substantial differences in tumor growth retardation and body weight change was observed between the treatments with targeted F8IL9F8 and the untargeted variant KSFIL9KSF (based on the irrelevant anti-hen egg lysozyme antibody KSF) ( Figure 3A). The CT26 model, recently described as an immunologically "hot" tumor [40], was investigated due to earlier reports demonstrating in vivo growth impairment of CT26 tumors ectopically expressing IL9 [14,15]. In order to investigate dose dependence effect of IL9 therapy, mice received three injections of F8IL9F8 at different doses, i.e.…”

Section: Radiolabeled Biodistribution and Tumor Therapiesmentioning

confidence: 99%

Antibody-based delivery of Interleukin-9 to neovascular structures: therapeutic evaluation in cancer and arthritis

Gouyou

Ongaro

Cazzamalli

et al. 2020

Preprint

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Interleukin-9 (IL9) is a cytokine with multiple functions, including the ability to activate group 2 innate lymphoid cells (ILC2s), which has been postulated to be therapeutically active in mouse models of arthritis. Similarly, IL9 has been suggested to play an important role in tumor immunity. Here, we describe the cloning, expression and characterization of three fusion proteins based on murine IL9 and the F8 antibody, specific to the alternatively-spliced EDA domain of fibronectin. EDA is strongly expressed in cancer and in various arthritic conditions, while being undetectable in the majority of healthy organs. IL9-based fusion proteins with an irrelevant antibody specific to hen egg lysozyme served as negative control in our study. The fusion proteins were characterized by quantitative biodistribution analysis in tumor-bearing mice using radioiodinated protein preparations. The highest tumor uptake and best tumor:organ ratios were observed for a format, in which the IL9 moiety was flanked by two units of the F8 antibody in single-chain Fv format. Biological activity of IL9 was retained when the payload was fused to antibodies. However, the targeted delivery of IL9 to the disease site resulted in a modest anti-tumor activity in three different murine models of cancer (K1735M2, CT26 and F9), while no therapeutic benefit was observed in a collagen induced model of arthritis. Collectively, these results confirm the possibility to deliver IL9 to the site of disease but cast doubts about the alleged therapeutic activity of this cytokine in cancer and arthritis, which has been postulated in previous publications.

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“…They found that the expression levels of IL-9 protein and messenger RNA were lower than those in the controls and correlated with TNM staging, Dukes staging, lymph node metastasis, and good prognosis. In vivo , IL-9 overexpression significantly inhibited tumor growth and resulted in a longer survival time in a mouse subcutaneous allograft model (80). Moreover, an ectopically expressed membrane-bound form of IL-9 induces an immunostimulatory effect that suppresses the growth of CT26 colon cancer cells (81).…”

Section: The Role Of Th9/il-9 Th17/il-17 and Th22/il-22 In The Devementioning

confidence: 99%

TH9, TH17, and TH22 Cell Subsets and Their Main Cytokine Products in the Pathogenesis of Colorectal Cancer

Cui

2019

Front. Oncol.

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In recent years, several newly identified T helper (TH) cell subsets, such as TH9, TH17, and TH22 cells, and their respective cytokine products, IL-9, IL-17, and IL-22, have been reported to play critical roles in the development of chronic inflammation in the colorectum. Since chronic inflammation is a potent driving force for the development of human colorectal cancer (CRC), the contributions of TH9/IL-9, TH17/IL-17, and TH22/IL-22 in the pathogenesis of CRC have recently become an increasingly popular area of scientific investigation. Extensive laboratory and clinical evidence suggests a positive relationship between these new TH subsets and the growth and formation of CRC, whereas, administration of IL-9, IL-17, and IL-22 signaling inhibitors can significantly alter the formation of colorectal chronic inflammation or CRC lesions in animal models, suggesting that blocking these cytokine signals might represent promising immunotherapeutic strategies. This review summarizes recent findings and currently available data for understanding the vital role and therapeutic significance of TH9/IL-9, TH17/IL-17, and TH22/IL-22 in the development of colorectal tumorigenesis.

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IL-9 Exerts Antitumor Effects in Colon Cancer and Transforms the Tumor Microenvironment In Vivo

Cited by 31 publications

References 46 publications

Significant and conflicting correlation of IL-9 withPrevotellaandBacteroidesin human colorectal cancer

Significant and conflicting correlation of IL-9 withPrevotellaandBacteroidesin human colorectal cancer

Antibody-based delivery of Interleukin-9 to neovascular structures: therapeutic evaluation in cancer and arthritis

TH9, TH17, and TH22 Cell Subsets and Their Main Cytokine Products in the Pathogenesis of Colorectal Cancer

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