Melanoma-Derived Interleukin 6 Inhibits In Vivo Melanoma Growth

Armstrong, Cheryl A.; Murray, Nancy B.; Kennedy, Michael; Koppula, S.; Tara, David; Ansel, John C.

doi:10.1111/1523-1747.ep12371782

Cited by 18 publications

(13 citation statements)

References 34 publications

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“…Studies in mast cell-deficient Kit W /Kit Wv mice, using the B16.BL6 melanoma model, demonstrated that delayed tumor growth kinetics in mast cell-deficient mice is attributable to a delayed and decreased angiogenic response (13). Mast cell IL-6-dependent angiogenesis suppression is consistent with previous findings that IL-6-mediated melanoma growth inhibition is independent of B and T cell responses (41) and that the antitumor action of IL-6 is due in part to angiogenesis inhibition (53). Further, IL-6-transfected B16.F10 tumors exhibit a significant decrease in angiogenesis via an in vivo intradermal angiogenesis assay (40).…”

Section: /2supporting

confidence: 89%

“…*p , 0.05. for several tumor cell types, including melanoma (38,(43)(44)(45). The melanoma growth-inhibitory effects of IL-6 have also been confirmed in vivo (40,41). Studies in melanoma cell lines, including B16.F10.9 cells, have demonstrated IL-6-induced tumor cell growth inhibition is enhanced in the presence of soluble IL-6R and occurs via a STAT-dependent mechanism that involves upregulation of cyclin-dependent kinase inhibitors and induction of cell cycle arrest (46)(47)(48).…”

Section: /2mentioning

confidence: 95%

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

Oldford

Haidl

Howatt

et al. 2010

The Journal of Immunology

118

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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 protumorigenic role. Tumor growth inhibition after peritumoral administration of Pam3CSK4 was restored in KitW-sh/W-sh 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, to our knowledge, a novel mechanism of action for TLR2 agonists in vivo.

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Section: /2supporting

confidence: 89%

Section: /2mentioning

confidence: 95%

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

Oldford

Haidl

Howatt

et al. 2010

The Journal of Immunology

118

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“…[46][47][48] However, IL-6 also inhibited the growth of immunogenic tumors by stimulating antitumor T-cell activity. [30][31][32]49,50 Similarly, several studies showed that IL-4 has a potent antitumor activity that does not appear to be T-cell dependent. 51,52 In contrast, a protumor activity of IL-4 mediated by Th2 lymphocytes has also been reported.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-17 inhibits tumor cell growth by means of a T-cell–dependent mechanism

Benchetrit

Cirée

Vives

et al. 2002

Blood

312

245

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IntroductionInterleukin-17 (IL-17), originally identified by Rouvier et al 1 as cytolytic T-lymphocyte (CTL)-associated antigen 8, is a T-cellderived cytokine with homology to Herpesvirus saimiri. [1][2] It is expressed mainly by activated CD4 ϩ CD45RO ϩ memory T cells. [3][4] CD4 T cells can be classified into T-helper (Th) 1 cells, which secrete interferon (IFN) ␥, IL-2, and tumor necrosis factor (TNF) ␤; Th2 cells, which produce IL-4, IL-5, IL-6, IL-10, and IL-13; and Th0 cells, a common precursor with the ability to release both IFN␥ and IL-4. Thirty percent of Th0/Th1 clones have been shown to produce IL-17, whereas Th2 clones never express IL-17. 5 IL-2 and IL-15 were found to increase IL-17 production by human peripheral blood (PB) mononuclear cells. 6 IL-17 is considered to be a proinflammatory cytokine because it increases IL-6 and IL-8 production by macrophages, fibroblasts, keratinocytes, and synovial cells 2,3,[7][8][9] and nitric oxide production by human osteoarthritic cartilage. 10,11 IL-17 also induces secretion of IL-1␤ and TNF-␣ by human macrophages and endothelial cells. 7,12 IL-17 activates the nuclear factor B and activator protein 1 transcription factors, which may explain its proinflammatory properties. 10,13 In addition, IL-17 induces production of granulocyte colony-stimulating factor and CXC chemokines that stimulate granulopoiesis and recruitment of neutrophils into tissues. [14][15][16] The IL-17 receptor is a type I transmembrane protein that is expressed in virtually all cells and tissues, in contrast to the restricted expression of IL-17, which is confined to T cells. 2,17 This receptor has no sequence similarity with any other known cytokine receptor. It interacts with the adapter molecule TNF receptorassociated factor 6, which is required for IL-17 signaling. 18 The exact role of IL-17 in disease is unknown. IL-17 has been found to promote cartilage destruction in various forms of arthritis. 19,20 Overproduction of IL-17 has been observed in the synovium of patients with rheumatoid arthritis 21 and in PB lymphocytes from patients with systemic sclerosis. 22 In a previous study, we found that IL-17 promotes tumorigenicity of human cervical tumors in nude mice. 23 Because this paradoxical tumor-promoting activity of IL-17 in the absence of T cells was unexpected, we conducted the current study to analyze the effect of IL-17 on the growth of syngeneic tumors in immunocompetent mice. We found that IL-17 inhibits the growth of 2 hematopoietic tumors, mastocytoma P815 and plasmocytoma Materials and methods Mice and tumor cell linesFemale Balb/c, DBA/2, and athymic nude/nude mice 6 to 8 weeks of age (Iffa Credo L'Arbresle, France) were used in this study. The mouse plasmocytoma J558L and mastocytoma P815 cell lines were obtained from the American Type Culture Collection (Manassas, VA). The mouse squamous cell carcinoma KLN 205 was purchased from the European Collection of Cell Culture (Salisbury, Wiltshire, United Kingdom). The cell lines were cultured in RPMI supplemented with 10% fet...

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“…B16 lines transfected by IL-6 genes also showed reduced tumor growth and increased tumor immunity (Mackiewicz et al, 1995b;Armstrong et al, 1994). Although T-cell depletion reduces the antitumoral response , some e ects of IL-6 transfected cells persisted in nude mice (Armstrong et al, 1994) suggesting that in addition to the immune-mediated indirect action there is also a direct e ect on tumor growth. Since sIL-6R circulates in body¯uids (Gaillard et al, 1993) we now consider it possible that, in vivo, endogenous sIL-6R elicited a direct e ect of IL-6 on the tumor cells.…”

Section: Il-6 Il-6+il-6r Treatmentmentioning

confidence: 99%

“…Screening of primary and established tumor cells for the sIL-6R e ect may be of interest, even though resistance to IL-6 growth inhibition is not always overcome by sIL-6R (Silvani et al, 1995) and may be due to high IRF-2/IRF-1 ratios (Harroch et al, 1993(Harroch et al, , 1994a. Nevertheless, considering that about 50% of advanced melanomas produce autocrine IL-6 (Colombo et al, 1992;Lu and Kerbel, 1993;Armstrong et al, 1994), sIL-6R may enhance IL-6 e ects of many tumor cells which have lost surface IL-6R due to autocrine IL-6 (Silvani et al, 1995) either by retention of IL-6R inside the cell (Rose-John et al, 1993) or by decrease in IL-6R mRNA (Ganapathi et al, 1996). On the other hand, since the agonist e ect of sIL-6R is seen also on cells with abundant IL-6 receptors (Novick et al, 1992), the actual mechanism of the sIL-6R agonist action may well be a catalytic acceleration of gp130 dimerization within the hexameric IL-6 receptor complex Halimi et al, 1995).…”

Section: Il-6 Il-6+il-6r Treatmentmentioning

confidence: 99%

Unmasking by soluble IL-6 receptor of IL-6 effect on metastatic melanoma: growth inhibition and differentiation of B16-F10.9 tumor cells

Katz

Harroch

et al. 1997

Oncogene

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Interleukin-6 (IL-6) inhibits the growth of melanocytes and of early stage melanoma cells, but not that of advanced melanoma cells. The in vitro IL-6 response can be restored in the highly metastatic melamona B16-F10.9 by addition of recombinant soluble IL-6 receptor a-chain (sIL-6R). The F10.9 cells then undergo irreversible growth-arrest and show increased adherence with changes from epithelioid to spindleoid morphology. The sIL-6R is required for IL-6 to induce a sustained activation of the various Stat transcription factors which bind to speci®c IL-6 inducible enhancers. The sIL-6R and IL-6 combination causes an increase in the level of the anti-oncogenic transcription factor IRF-1 protein and DNA-binding, which remain elevated for 24 h. The promoter activity of the anti-oncogenic p21/Waf-1/Cip-1 gene is induced and accumulation of the p21 protein is observed. These results illustrate the potent agonist activity of sIL-6R on molecular pathways which could mediate the growth-arrest and di erentiation of the metastatic melanoma cells. Previously observed antimetastatic e ects of IL-6 therapy in mice bearing F10.9 tumors may be at least partly due to direct growth inhibition and di erentiation elicited by sIL-6R present in biological¯uids.

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Melanoma-Derived Interleukin 6 Inhibits In Vivo Melanoma Growth

Cited by 18 publications

References 34 publications

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

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

Interleukin-17 inhibits tumor cell growth by means of a T-cell–dependent mechanism

Unmasking by soluble IL-6 receptor of IL-6 effect on metastatic melanoma: growth inhibition and differentiation of B16-F10.9 tumor cells

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