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Inhibition of Tumor Growth Cell-Derived IL-6 in TLR2-Mediated a Critical Role for Mast Cells and Mast

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Inhibition of Tumor Growth Cell-Derived IL-6 in TLR2-Mediated a Critical Role for Mast Cells and Mast A Critical Role for Mast Cells and Mast Cell-Derived IL-6 in TLR2-Mediated Inhibition of Tumor Growth This information is current as Sharon A. Oldford, Ian D. Haidl, Mackenzie A. Howatt, of September 28, 2021. Carlos A. Leiva, Brent Johnston and Jean S. Marshall J Immunol 2010; 185:7067-7076; Prepublished online 1 November 2010; doi: 10.4049/jimmunol.1001137 http://www.jimmunol.org/content/185/11/7067 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/11/01/jimmunol.100113 Material 7.DC1 http://www.jimmunol.org/ References This article cites 62 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/185/11/7067.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 28, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology A Critical Role for Mast Cells and Mast Cell-Derived IL-6 in TLR2-Mediated Inhibition of Tumor Growth Sharon A. Oldford,*,† Ian D. Haidl,*,† Mackenzie A. Howatt,*,† Carlos A. Leiva,*,† Brent Johnston,*,†,‡,x and Jean S. Marshall*,†,x 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 KitW-sh/W-sh mice and a complementary Matrigel–tumor model in C57BL/6 mice, mast cells were shown to be crucial for TLR2 agonist (Pam3CSK4)-induced tumor inhibition. Activation of TLR2 on mast cells reversed their well-documented W-sh/W-sh Downloaded from protumorigenic role. Tumor growth inhibition after peritumoral administration of Pam3CSK4 was restored in Kit mice by local reconstitution with wild-type, but not TLR2-deficient, mast cells. Mast cells secrete multiple mediators after Pam3CSK4 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, http://www.jimmunol.org/ to our knowledge, a novel mechanism of action for TLR2 agonists in vivo. The Journal of Immunology, 2010, 185: 7067–7076. he use of TLR agonists as immunological adjuvants in play a role in allergic disease and function as sentinel cells involved the treatment of cancer has been intensively studied. TLR- in the induction and development of effective immunity (7–9). T based immunotherapies have shown promise clinically Mast cells also play a role in tumorigenesis. Abundant mast cells are for the treatment of multiple tumor types. Specifically, TLR2 closely associated with blood vessels surrounding solid tumors and agonists have been successfully used as potential therapeutics in often correlate with enhanced tumor angiogenesis and poor prog- animal models of pancreatic and brain carcinoma (1, 2) as well as nosis (10–12). Studies using mast cell-deficient KitW/KitWv or by guest on September 28, 2021 in clinical trials (3). In general, the successful mechanism of ac- KitW-sh/KitW-sh mice showed that tumor-associated mast cells are tion of TLR agonists is considered to involve dendritic cell mat- potent tumor angiogenesis promoters, enhancing tumor growth uration with enhanced tumor Ag presentation and generation of and metastasis (13–15). Although extensive studies demonstrate a Th1 immunity and CD8 antitumor effector cells (4). TLR2 ago- protumorigenic role for mast cells (reviewed in Ref. 16), antitumor nists, such as Pam3CSK4, often do not share the strong Th1 po- actions of mast cells have also been reported. In vitro studies larizing effects of other TLR agonists (5, 6). However, they retain have demonstrated mast cells can mediate direct TNF-mediated effectiveness in tumor immunotherapy models, opening up the tumor cell cytotoxicity (17, 18). Several studies have also corre- possibility that they have a distinct mechanism of action. lated high mast cell density with improved survival (19–21). The Mast cells are localized at body sites that interface with the en- conflicting reports of associations of mast cells with prognosis are vironment, such as the skin and mucous membranes, where they potentially largely dependent on effects of the local tumor micro- environment on mast cell activation status and mediator release. During infection, activation of mast cell receptors including Fcg *Dalhousie Inflammation Group, †Department of Microbiology and Immunology, receptors, complement receptors, and TLRs results in the release of ‡ x Department of Pediatrics, and Department of Pathology, Dalhousie University, Hal- preformed mediators including histamine and proteases, the syn- ifax, Nova Scotia B3H 1X5, Canada thesis of lipid mediators, and the selective production of multiple Received for publication April 8, 2010. Accepted for publication September 28, 2010. cytokines and chemokines. These mediators are important in elim- inating pathogens, recruiting other leukocytes such as neutro- This work was supported by funding from the Canadian Cancer Society Research Institute and the Canadian Institutes of Health Research. S.A.O. was supported by phils, NK cells, and T cells, increasing vascular permeability, and a Canadian Institutes of Health Research-funded Strategic Training in Health Re- in mediating proteolytic degradation at the site of infection (9). search Initiative and by the Nova Scotia Health Research Foundation. Although the role of mast cells in protecting against infection is Address correspondence and reprint requests to Dr. Jean S. Marshall, Department of well documented, the effects of activating mast cells in the context Microbiology and Immunology, Faculty of Medicine, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada. E-mail of tumorigenesis have not been substantially explored. address: [email protected] Mast cells are prevalent in the skin and are abundant at the pe- The online version of this article contains supplemental material. riphery of melanomas (12). They respond to TLR2 agonists by Abbreviations used in this paper: BMMC, bone marrow-derived mast cell; CPT, producing leukotrienes, cytokines, and chemokines, which could camptothecin; ns, not significant; PI, propidium iodide; RFU, relative fluorescent modify the local microenvironment and recruit leukocytes poten- units; SA, streptavidin; Treg, regulatory T cell; UD, undetectable. tially to limit tumor growth (22, 23). We therefore investigated the Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 role of the mast cell in the tumor growth-inhibitory effects of the www.jimmunol.org/cgi/doi/10.4049/jimmunol.1001137 7068 ACTIVATED MAST CELLS INHIBIT TUMOR GROWTH TLR2/1 agonist Pam3CSK4 using an orthotopic model of B16.F10 blood was collected, tumors were excised and digested in 300 U/ml col- melanoma, a well used, highly aggressive, poorly immunogenic lagenase IV (Sigma-Aldrich), and cell-free supernatants were measured tumor (24). B16.F10 growth was compared in wild-type and fluorometrically (excitation 488 nm, emission 519 nm). Relative fluores- cent units (RFU) were normalized to blood plasma levels. mast cell-deficient KitW-sh/W-sh mice. Although KitW-sh/W-sh mice are mainly white, they are suitable for melanoma growth studies as the Histology W-sh Kit mutation impairs long-term endogenous melanocyte survival Formalin-fixed, paraffin-embedded Matrigel–tumor sections (3 mm) were but does not affect melanoblast development or differentiation or stained with H&E. Mature erythrocyte-containing blood vessel lumens the survival of transplanted c-Kit–expressing melanocytes. Homo- were quantified in non-overlapping fields (magnification 3400) of tumor zygote adult animals consistently retain melanocytes at selected periphery, on coded sections. Mast cells were visualized using Alcian blue (pH 0.5)–safranin O staining of Carnoy’s fixed, paraffin-embedded tumor sites including the ear pinna (25, 26). Comparative growth studies in sections. W-sh/W-sh Kit and control C57BL/6 mice identified that Pam3CSK4 inhibits tumor growth in a mast cell and mast cell-derived IL-6-de- Tumor cell cytotoxicity and cell viability pendent manner. This study demonstrates that selective activation Tumor cell proliferation was evaluated by the MTT assay. Briefly, 1 3 104 of mast cells via TLR2 can reverse their tumor-promoting potential tumor cells were incubated overnight in 96-well tissue culture plates then and induce them to inhibit tumor growth. treated, in quadruplicate, for 24 h before MTT addition. Treatments in- cluded 0, 1, or 10 mg/ml Pam3CSK4,5mg/ml of the DNA topoisomerase I inhibitor camptothecin (CPT) or DMSO vehicle control (Sigma-Aldrich), Materials and Methods or supernatants from C57BL/6 or IL-62/2 BMMCs incubated for 24 h in Mice BMMC culture medium with or without 10 mg/ml Pam3CSK4.
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