A critical role for mast cells and mast cell-derived IL-6 in TLR2-mediated inhibition of tumor growth

Several TLR agonists are effective in tumor immunotherapy, but their early innate mechanisms of action, particularly those of TLR2 agonists, are unclear. Mast cells are abundant surrounding solid tumors where they are often protumorigenic and enhance tumor angiogenesis. However, antitumor roles for...

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Bibliographic Details
Published in:	The Journal of immunology (1950) Vol. 185; no. 11; pp. 7067 - 7076
Main Authors:	Oldford, Sharon A, Haidl, Ian D, Howatt, Mackenzie A, Leiva, Carlos A, Johnston, Brent, Marshall, Jean S
Format:	Journal Article
Language:	English
Published:	United States 01-12-2010
Subjects:	Animals Antineoplastic Agents - agonists Antineoplastic Agents - therapeutic use Bone Marrow Cells - immunology Bone Marrow Cells - metabolism Bone Marrow Cells - pathology Cell Line, Tumor Cells, Cultured Female Growth Inhibitors - agonists Growth Inhibitors - deficiency Growth Inhibitors - therapeutic use Interleukin-6 - deficiency Interleukin-6 - genetics Interleukin-6 - physiology Lung Neoplasms - immunology Lung Neoplasms - pathology Lung Neoplasms - therapy Male Mast Cells - immunology Mast Cells - metabolism Mast Cells - pathology Melanoma, Experimental - immunology Melanoma, Experimental - pathology Melanoma, Experimental - therapy Mice Mice, Inbred C57BL Mice, Knockout Mice, Mutant Strains Toll-Like Receptor 2 - agonists Toll-Like Receptor 2 - deficiency Toll-Like Receptor 2 - therapeutic use
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Summary:	Several TLR agonists are effective in tumor immunotherapy, but their early innate mechanisms of action, particularly those of TLR2 agonists, are unclear. Mast cells are abundant surrounding solid tumors where they are often protumorigenic and enhance tumor angiogenesis. However, antitumor roles for mast cells have also been documented. The impact of mast cells may be dependent on their activation status and mediator release in different tumors. Using an orthotopic melanoma model in wild-type C57BL/6 and mast cell-deficient Kit(W-sh/W-sh) mice and a complementary Matrigel-tumor model in C57BL/6 mice, mast cells were shown to be crucial for TLR2 agonist (Pam(3)CSK(4))-induced tumor inhibition. Activation of TLR2 on mast cells reversed their well-documented protumorigenic role. Tumor growth inhibition after peritumoral administration of Pam(3)CSK(4) was restored in Kit(W-sh/W-sh) mice by local reconstitution with wild-type, but not TLR2-deficient, mast cells. Mast cells secrete multiple mediators after Pam(3)CSK(4) activation, and in vivo mast cell reconstitution studies also revealed that tumor growth inhibition required mast cell-derived IL-6, but not TNF. Mast cell-mediated anticancer properties were multifaceted. Direct antitumor effects in vitro and decreased angiogenesis and recruitment of NK and T cells in vivo were observed. TLR2-activated mast cells also inhibited the growth of lung cancer cells in vivo. Unlike other immune cells, mast cells are relatively radioresistant making them attractive candidates for combined treatment modalities. This study has important implications for the design of immunotherapeutic strategies and reveals, to our knowledge, a novel mechanism of action for TLR2 agonists in vivo.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0022-1767 1550-6606
DOI:	10.4049/jimmunol.1001137