IL-31 induces antitumor immunity in breast carcinoma
Background Immunomodulatory agents that induce antitumor immunity have great potential for treatment of cancer. We have previously shown that interleukin (IL)-31, a proinflammatory cytokine from the IL-6 family, acts as an antiangiogenic agent. Here, we characterize the immunomodulatory effect of IL...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e001010.full |
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| author | Tal Kan Erik Feldman Michael Timaner Ziv Raviv Shai Shen-Orr Ami Aronheim Yuval Shaked |
| author_facet | Tal Kan Erik Feldman Michael Timaner Ziv Raviv Shai Shen-Orr Ami Aronheim Yuval Shaked |
| author_sort | Tal Kan |
| collection | DOAJ |
| description | Background Immunomodulatory agents that induce antitumor immunity have great potential for treatment of cancer. We have previously shown that interleukin (IL)-31, a proinflammatory cytokine from the IL-6 family, acts as an antiangiogenic agent. Here, we characterize the immunomodulatory effect of IL-31 in breast cancer.Methods In vivo breast carcinoma models including EMT6 and PyMT cell lines were used to analyze the effect of IL-31 on the composition of various immune cells in the tumor microenvironment using high-throughput flow cytometry. In vitro studies using isolated cytotoxic T cells, CD4+ T cells, myeloid-derived suppressor cells (MDSCs) and macrophages were carried out to study IL-31 immunological activity. The generation of recombinant IL-31 bound to IgG backbone was used to test IL-31 therapeutic activity.Results The growth rate of IL-31-expressing breast carcinomas is decreased in comparison with control tumors due, in part, to antitumor immunomodulation. Specifically, cytotoxic T cell activity is increased, whereas the levels of CD4+ T cells, MDSCs, and tumor-associated macrophages are decreased in IL-31-expressing tumors. These cellular changes are accompanied by a cytokine profile associated with antitumor immunity. In vitro, IL-31 directly inhibits CD4+ Th0 cell proliferation, and the expression of Th2 canonical factors GATA3 and IL-4. It also promotes CD8+ T cell activation through inhibition of MDSC activity and motility. Clinically, in agreement with the mouse data, alterations in immune cell composition in human breast cancer biopsies were found to correlate with high expression of IL-31 receptor A (IL-31Ra) . Furthermore, high coexpression of IL-31Ra, IL-2 and IL-4 in tumors correlates with increased survival. Lastly, to study the therapeutic potential of IL-31, a recombinant murine IL-31 molecule was fused to IgG via a linker region (IL-31-L-IgG). This IL-31-L-IgG therapy demonstrates antitumor therapeutic activity in a murine breast carcinoma model.Conclusions Our findings demonstrate that IL-31 induces antitumor immunity, highlighting its potential utility as a therapeutic immunomodulatory agent. |
| format | Article |
| id | doaj-art-7d9ec16b9d2a4589b68fcef2e01d3fdd |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-7d9ec16b9d2a4589b68fcef2e01d3fdd2024-11-09T22:00:11ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-001010IL-31 induces antitumor immunity in breast carcinomaTal Kan0Erik Feldman1Michael Timaner2Ziv Raviv3Shai Shen-Orr4Ami Aronheim5Yuval Shaked6Novocure Ltd, Haifa, IsraelTechnion-integrated cancer center, Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelFaculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelTechnion-integrated cancer center, Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel3 Department of Immunology, Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelTechnion-integrated cancer center, Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelFaculty of Medicine, Technion Israel Institute of Technology, Haifa, IsraelBackground Immunomodulatory agents that induce antitumor immunity have great potential for treatment of cancer. We have previously shown that interleukin (IL)-31, a proinflammatory cytokine from the IL-6 family, acts as an antiangiogenic agent. Here, we characterize the immunomodulatory effect of IL-31 in breast cancer.Methods In vivo breast carcinoma models including EMT6 and PyMT cell lines were used to analyze the effect of IL-31 on the composition of various immune cells in the tumor microenvironment using high-throughput flow cytometry. In vitro studies using isolated cytotoxic T cells, CD4+ T cells, myeloid-derived suppressor cells (MDSCs) and macrophages were carried out to study IL-31 immunological activity. The generation of recombinant IL-31 bound to IgG backbone was used to test IL-31 therapeutic activity.Results The growth rate of IL-31-expressing breast carcinomas is decreased in comparison with control tumors due, in part, to antitumor immunomodulation. Specifically, cytotoxic T cell activity is increased, whereas the levels of CD4+ T cells, MDSCs, and tumor-associated macrophages are decreased in IL-31-expressing tumors. These cellular changes are accompanied by a cytokine profile associated with antitumor immunity. In vitro, IL-31 directly inhibits CD4+ Th0 cell proliferation, and the expression of Th2 canonical factors GATA3 and IL-4. It also promotes CD8+ T cell activation through inhibition of MDSC activity and motility. Clinically, in agreement with the mouse data, alterations in immune cell composition in human breast cancer biopsies were found to correlate with high expression of IL-31 receptor A (IL-31Ra) . Furthermore, high coexpression of IL-31Ra, IL-2 and IL-4 in tumors correlates with increased survival. Lastly, to study the therapeutic potential of IL-31, a recombinant murine IL-31 molecule was fused to IgG via a linker region (IL-31-L-IgG). This IL-31-L-IgG therapy demonstrates antitumor therapeutic activity in a murine breast carcinoma model.Conclusions Our findings demonstrate that IL-31 induces antitumor immunity, highlighting its potential utility as a therapeutic immunomodulatory agent.https://jitc.bmj.com/content/8/2/e001010.full |
| spellingShingle | Tal Kan Erik Feldman Michael Timaner Ziv Raviv Shai Shen-Orr Ami Aronheim Yuval Shaked IL-31 induces antitumor immunity in breast carcinoma Journal for ImmunoTherapy of Cancer |
| title | IL-31 induces antitumor immunity in breast carcinoma |
| title_full | IL-31 induces antitumor immunity in breast carcinoma |
| title_fullStr | IL-31 induces antitumor immunity in breast carcinoma |
| title_full_unstemmed | IL-31 induces antitumor immunity in breast carcinoma |
| title_short | IL-31 induces antitumor immunity in breast carcinoma |
| title_sort | il 31 induces antitumor immunity in breast carcinoma |
| url | https://jitc.bmj.com/content/8/2/e001010.full |
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