Interleukin-33 is a Novel Immunosuppressor that Protects Cancer Cells from TIL Killing by a Macrophage-Mediated Shedding Mechanism

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.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