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However, this process can be affected by other non\u2010cancerous cellular components in the tumor microenvironment. Here, it is shown that interleukin\u201033 (IL\u201033)\u2010activated macrophages protect melanoma cells from tumor\u2010infiltrating lymphocyte\u2010mediated killing. Mechanistically, IL\u201033 markedly upregulates metalloprotease 9 (MMP\u20109) 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 <jats:italic>\u03b3\u03b4<\/jats:italic> T cells. Further, MMP\u20109 also cleaves the MHC class I molecule, cell surface antigen\u2010presenting complex molecules, expressed in melanoma cells. Consequently, IL\u201033\u2010induced macrophage MMP\u20109 robustly mitigates the tumor killing\u2010effect by T cells. Genetic and pharmacological loss\u2010of\u2010function of MMP\u20109 sheddase restore T cell\u2010mediated cancer killing. Together, these data provide compelling in vitro and in vivo evidence showing novel mechanisms underlying the IL\u201033\u2010macrophage\u2010MMP\u20109 axis\u2010mediated immune tolerance against cancer cells. Targeting each of these signaling components, including IL\u201033 and MMP\u20109 provides a new therapeutic paradigm for improving anticancer efficacy by immune therapy.<\/jats:p>","DOI":"10.1002\/advs.202101029","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T02:57:06Z","timestamp":1630897026000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Interleukin\u201033 is a Novel Immunosuppressor that Protects Cancer Cells from TIL Killing by a Macrophage\u2010Mediated Shedding Mechanism"],"prefix":"10.1002","volume":"8","author":[{"given":"Jing","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Microbiology Tumor and Cell Biology Karolinska Institute  Stockholm 171 65 Sweden"},{"name":"Department of Pharmacy The Second Hospital of Shandong University  Jinan Shandong 250000 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