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Interleukin-33 is a...
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Wu, JingKarolinska Institutet
(author)
Interleukin-33 is a Novel Immunosuppressor that Protects Cancer Cells from TIL Killing by a Macrophage-Mediated Shedding Mechanism
- Article/chapterEnglish2021
Publisher, publication year, extent ...
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2021-09-05
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Wiley,2021
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electronicrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:liu-179136
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-179136URI
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https://doi.org/10.1002/advs.202101029DOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:147540347URI
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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Funding Agencies|European Research Council (ERC) advanced grant ANGIOFATEuropean Research Council (ERC) [250021]; Swedish Research CouncilSwedish Research CouncilEuropean Commission; Swedish Cancer Foundation; Swedish Childrens Cancer Foundation; Strategic Research Areas (SFO)-Stem Cell and Regenerative Medicine Foundation; Karolinska Institute FoundationKarolinska Institutet; Karolinska Institute distinguished professor awardKarolinska Institutet; Torsten Soderbergs Foundation; Maud and Birger Gustavsson Foundation; NOVO Nordisk Foundation-Advance grantNovo Nordisk; NOVO Nordisk FoundationNovo Nordisk Foundation; Knut and Alice Wallenbergs FoundationKnut & Alice Wallenberg Foundation; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81801163, 81703617]; Jinan clinical medical science and technology innovation plan [202019099]; China Scholarship CouncilChina Scholarship Council [201906225024]; Karolinska InstituteKarolinska Institutet
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Recognition of specific antigens expressed in cancer cells is the initial process of cytolytic T cell-mediated cancer killing. However, this process can be affected by other non-cancerous cellular components in the tumor microenvironment. Here, it is shown that interleukin-33 (IL-33)-activated macrophages protect melanoma cells from tumor-infiltrating lymphocyte-mediated killing. Mechanistically, IL-33 markedly upregulates metalloprotease 9 (MMP-9) expression in macrophages, which acts as a sheddase to trim NKG2D, an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, subsets of CD4+ T cells, iNKT cells, and gamma delta T cells. Further, MMP-9 also cleaves the MHC class I molecule, cell surface antigen-presenting complex molecules, expressed in melanoma cells. Consequently, IL-33-induced macrophage MMP-9 robustly mitigates the tumor killing-effect by T cells. Genetic and pharmacological loss-of-function of MMP-9 sheddase restore T cell-mediated cancer killing. Together, these data provide compelling in vitro and in vivo evidence showing novel mechanisms underlying the IL-33-macrophage-MMP-9 axis-mediated immune tolerance against cancer cells. Targeting each of these signaling components, including IL-33 and MMP-9 provides a new therapeutic paradigm for improving anticancer efficacy by immune therapy.
Subject headings and genre
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Chen, ZiqingKarolinska Inst, Sweden
(author)
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Wickström, Stina L.Karolinska Institutet
(author)
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Gao, JuanKarolinska Institutet
(author)
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He, XingkangKarolinska Inst, Sweden; Zhejiang Univ, Peoples R China
(author)
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Jing, XuKarolinska Institutet
(author)
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Wu, JieyuKarolinska Inst, Sweden
(author)
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Du, QiqiaoKarolinska Inst, Sweden
(author)
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Yang, MuyiKarolinska Institutet
(author)
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Chen, YiKarolinska Inst, Sweden
(author)
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Zhang, DingdingKarolinska Inst, Sweden; Univ Elect Sci & Technol China, Peoples R China
(author)
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Yin, XinKarolinska Inst, Sweden
(author)
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Guo, ZihengSichuan Univ, Peoples R China
(author)
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Jensen, LasseLinköpings universitet,Avdelningen för diagnostik och specialistmedicin,Medicinska fakulteten,Region Östergötland, Klinisk farmakologi(Swepub:liu)larje86
(author)
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Yang, YunlongKarolinska Institutet
(author)
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Tao, WeiHarvard Med Sch, MA 02115 USA; Harvard Med Sch, MA 02115 USA
(author)
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Lundqvist, AndreasKarolinska Institutet
(author)
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Kiessling, RolfKarolinska Institutet
(author)
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Cao, YihaiKarolinska Inst, Sweden
(author)
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Karolinska InstitutetKarolinska Inst, Sweden
(creator_code:org_t)
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In:Advanced Science: Wiley8:212198-3844
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Wu, Jing
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Chen, Ziqing
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Wickström, Stina ...
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Gao, Juan
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He, Xingkang
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Jing, Xu
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Wu, Jieyu
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Du, Qiqiao
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Yang, Muyi
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Chen, Yi
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Zhang, Dingding
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Yin, Xin
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Guo, Ziheng
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Jensen, Lasse
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Yang, Yunlong
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Tao, Wei
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Lundqvist, Andre ...
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Kiessling, Rolf
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Cao, Yihai
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Advanced Science
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Karolinska Institutet