title: The combined action of mast cell chymase, tryptase and carboxypeptidase A3 protects against melanoma colonization of the lung.
abstract: Mast cell secretory granules are densely packed with various bioactive mediators including proteases of chymase, tryptase and CPA3 type. Previous studies have indicated that mast cells can affect the outcome of melanoma but the contribution of the mast cell granule proteases to such effects has not been clear. Here we addressed this issue by assessing mice lacking either the chymase Mcpt4, the tryptase Mcpt6 or carboxypeptidase A3 (Cpa3), as well as mice simultaneously lacking all three proteases, in a model of melanoma dissemination from blood to the lung. Although mice with individual deficiency in the respective proteases did not differ significantly from wildtype mice in the extent of melanoma colonization, mice with multiple protease deficiency (Mcpt4/Mcpt6/Cpa3-deficient) exhibited a higher extent of melanoma colonization in lungs as compared to wildtype animals. This was supported by higher expression of melanoma-specific genes in lungs of Mcpt4/Mcpt6/CPA3-deficient vs. wildtype mice. Cytokine profiling showed that the levels of CXCL16, a chemokine with effects on T cell populations and NKT cells, were significantly lower in lungs of Mcpt4/Mcpt6/Cpa3-deficient animals vs. controls, suggesting that multiple mast cell protease deficiency might affect T cell or NKT cell populations. In line with this, we found that the Mcpt4/Mcpt6/Cpa3-deficiency was associated with a reduction in cells expressing CD1d, a MHC class 1-like molecule that is crucial for presenting antigen to invariant NKT (iNKT) cells. Together, these findings indicate a protective role of mast cell-specific proteases in melanoma dissemination, and suggest that this effect involves a CXCL16/CD1d/NKT cell axis.
authors.affiliation: Uppsala University, Department of Medical Biochemistry and Microbiology, Uppsala, Sweden.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Grujic
authors.affiliation: Uppsala University, Department of Medical Biochemistry and Microbiology, Uppsala, Sweden.
authors.forename: Aida
authors.initials: A
authors.lastname: Paivandy
authors.affiliation: Uppsala University, Department of Medical Biochemistry and Microbiology, Uppsala, Sweden.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Gustafson
authors.affiliation: University of Copenhagen, Department of Immunology and Microbiology, Copenhagen, Denmark.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Thomsen
authors.affiliation: Uppsala University, Department of Medical Biochemistry and Microbiology, Uppsala, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Öhrvik
authors.affiliation: Uppsala University, Department of Medical Biochemistry and Microbiology, Uppsala, Sweden.|Swedish University of Agricultural Sciences, Department of Anatomy, Physiology and Biochemistry, Uppsala, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Pejler
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism; D043422:Carboxypeptidases A / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000075743:Chemokine CXCL16 / Q000378:metabolism; D053818:Chymases / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control / Q000556:secondary*; D008407:Mast Cells / Q000201:enzymology*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008546:Melanoma, Experimental; D051379:Mice; D018345:Mice, Knockout; D009367:Neoplasm Staging; D053802:Tryptases / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden
chemical_list: D055610:Antigens, CD1d; D000075743:Chemokine CXCL16; D043422:Carboxypeptidases A; D053818:Chymases; D053802:Tryptases
keywords: CD1d; carboxypeptidase A3; chymase; mast cells; tryptase