- Email: [email protected]
Breaking Immunological Tolerance to Melanocyte Differentiation Antigens by Hypopigmenting Agents: A New Means for Melanoma Immunotherapy?
commentary
Mengel-From J, Wong TH, Morling N et al. (2009) Genetic determinants of hair and eye colours in the Scottish and Danish populations. BMC Genet 10:88 Pan H, Wang Z, He B et al. (2010) Identification of a novel mutation in the DSRAD gene in a Chinese family with dyschromatosis symmetrica hereditaria. J Am Acad Dermatol 63:529–30 Shishido E, Kadono S, Manaka I et al. (2001) The mechanism of epidermal hyperpigmentation in dermatofibroma is associated with stem cell factor and hepatocyte growth factor expression. J Invest Dermatol 117:627–33
Stuhrmann M, Hennies HC, Bukhari IA et al. (2008) Dyschromatosis universalis hereditaria: evidence for autosomal recessive inheritance and identification of a new locus on chromosome 12q21–q23. Clin Genet 73:566–72 Wang XP, Liu Y, Wang JM et al. (2010) Two novel splice site mutations of the ADAR1 gene in Chinese families with dyschromatosis symmetrica hereditaria. J Dermatol 37:1051–2 Yamaguchi Y, Hearing VJ (2009) Physiological factors that regulate skin pigmentation. Biofactors 35:193–9
See related article on pg 1240
Breaking Immunological Tolerance to Melanocyte Differentiation Antigens by Hypopigmenting Agents: A New Means for Melanoma Immunotherapy? Jürgen C. Becker1 and David Schrama1 The hypopigmenting agent monobenzone induces inflammatory responses only in pigmented skin as well as depigmentation in areas not directly exposed to the drug. Both observations have been ascribed to the possible induction of adaptive immune responses against melanocytes. In this issue, van den Boorn et al. provide direct evidence confirming this hypothesis. Since the monobenzoneinduced immune responses target melanocyte-differentiation antigens, this report opens the opportunity for a simple and instantaneous deployable immunotherapy of melanoma. Journal of Investigative Dermatology (2011) 131, 1185–1187. doi:10.1038/jid.2011.94
Skin pigmentation depends primarily on the amount and type of melanin synthesized by melanocytes located in the basal layer of the epidermis and its distribution toward the surface of the epidermis (Yamaguchi et al., 2007). Melanin is synthesized within a specialized organelle, the melanosome. The essential enzyme in its synthesis is tyrosinase, a melanosomal membrane glycoprotein that catalyzes the initial and rate-limiting steps of melano
genesis. Ultimately, melanin packed in melanosomes is transferred from the melanocytes to adjacent keratinocytes. Agents to control skin pigmentation are used to address a variety of medical conditions, such as acquired hyperpigmentation and vitiligo (Hartmann et al., 2004). Hypopigmenting agents include hydroquinone or its monobenzyl ether, monobenzone (Solano et al., 2006); the drug Benoquin, manufactured by ICN, contains 20% monobenzone.
Department of General Dermatology, Medical University of Graz, Graz, Austria
1
Correspondence: Jürgen C. Becker, Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, A-8036 Graz, Austria. E-mail: [email protected]
More than 25 years ago, Nordlund et al. reported six patients with spreading vitiligo treated with applications of monobenzone who subsequently developed a vesicular dermatitis (Nordlund et al., 1985). Interestingly, the eruption was restricted to the pigmented areas of the skin. Patch tests applied to pigmented and depigmented skin produced inflammatory responses only within the pigmented areas, indicating that the effect depends on the presence of melanocytes. In this issue, van den Boorn et al. provide an explanation for this puzzling phenomenon (Figure 1). Application of monobenzone induces local depigmentation within 2 weeks, extending within a few months, however, to nonexposed skin sites. This observation indicates that monobenzone-induced depigmentation is not only based on direct effects on melanocytes but also involves a systemic process. Histological examination of biopsies obtained from monobenzone-treated skin revealed CD8+ T-cell infiltrates similar to those observed in spontaneous vitiligo or melanoma-associated hypopigmentation (Hartmann et al., 2008), thereby providing the first clue that the systemic effect probably results from an immunological process. The direct effect of monobenzone is attributed to inhibition of tyrosinase activity. Indeed, van den Boorn et al. (2011, this issue) demonstrated that tyrosinase metabolized monobenzone to 4-benzoxy-1,2-benzoquinone, which in turn inactivates tyrosinase by formation of quinone hapten binding to tyrosinase cysteine residues. Thus, monobenzone exposure reduces pigment-cell melano genesis without exerting selective toxicity. Notably, reactive benzene metabolites such as quinones are effective contact sensitizers, binding to proteins and forming hapten–carrier complexes that trigger hapten-specific immune responses (Ezendam et al., 2003). Consequently, van den Boorn et al. investigated the effects of monobenzone on the immunogenicity of pigmented cells, i.e., melanocytes and melanoma cells. Exposure to monobenzone induced reactive oxygen species exclusively in pigmented cells, associated with an increased release of tyrosinase- and MART-1-containing CD63+ exosomes. Exosomes are known www.jidonline.org 1185
commentary
Melanocyte dendrites
Melanin
Melanosome
Autophagosome Quinone hapten
Tyr
CD63 Release Tyrosine/ MHC class II complex
PIGMENTED CELL
Lysosomal degradation
O
EXOSOME
Reactive oxygen species ⋅OH
Monobenzone
Exosome endocytosis
O 2–⋅ H2O2
OH
Peptide/ MHC class I Tyrosinase
ATP release
H 2N O
O P O P O P O O
Ub Ub Ub
–
O
–
O
N
N
O
O
–
–
N
N
Adenosine triphosphate
O
IMMATURE DENDRITIC CELL
OH OH
NALP3 inflammasome Tyrosine/ MHC class I complex
Pigmented cellreactive CD8+ T-cell response
CD8+ T CELL
MATURE DENDRITIC CELL
Figure 1. Different effects of monobenzone treatment on pigmented cells. Tyrosinase (Tyr.), the rate limiting enzyme in the synthesis of melanin in melanosomes, catalyzes metabolite formation of monobenzone. Quinone haptens derived from the metabolite 4-benzoxy-1,2-benzoquinone bind to tyrosinase cysteine residues which leads to reduced melanin synthesis (upper left corner). In addition, augmented ubiquitination (Ub) of tyrosinase protein by monobenzone exposure enhances the presentation of this enzyme by MHC class I (lower left corner). Monobenzone induces reactive oxygen species (ROS) exclusively in pigmented cells. These ROS provoke the increased release of tyrosinase and Mart-1 containing exosomes and adenosine triphosphate (ATP) as well as melanosome autophagy. The autophagocytic response targets melanosomal tyrosinase protein via lysosomal degradation to MHC class‑II compartments (upper right). Immature dendritic cells will be activated upon endocytosis of quinone-haptenated tyrosinase containing exosomes triggering the NALP3 inflammasome. In addition, ATP released from monobenzone exposed cells will stimulate activation of the inflammasome (lower right). These activated and pigmented cell antigen presenting dendritic cells are then capable of inducing a specific immune response (lower middle). MHC, major histocompatibility complex.
to induce specific immunity (Thery et al., 2009). Moreover, monobenzone also affects antigen processing in pigmented cells by (i) induction of polyubiquit ination of tyrosinase, thereby enhancing its presentation in the major histo compatibility complex class I pathway, and (ii) formation of melanin-containing autophagosomes and autolysosomes. This autophagocytic response was found to target melanosomal tyrosinase protein via lysosomal degradation to major histocompatibility complex class II compartments. The impact of these monobenzoneinduced processes on the induction of cellular immune responses was confirmed by a series of cross-presentation experiments using immature human dendritic cells (DCs) and autologous naive T cells. These experiments demonstrated
that, in contrast to unexposed melanoma cells, intact monobenzone-exposed melanoma cells activated DCs that had taken up exosomes from these cells. Subsequently, these DCs, cultivated with lymphocytes from healthy human donors, induced a robust melanomareactive CD8+ T-cell response within 7 days in vitro. Notably, the induced
T-cell response was not restricted to monobenzone-treated melanoma cells (i.e., specific for epitopes linked to quinone hapten) because unexposed melanoma cells were recognized as well. However, the increased exosome secretion alone cannot account for the observed DC activation by monobenzone-exposed melanoma cells. Thus, it is important to note that monobenzoneexposed pigmented cells may activate DCs in two ways: (i) DC uptake of quinone-haptenated tyrosinase-containing exosomes augments DC activation via additional triggering of the NALP3 inflammasome and (ii) the generation of reactive oxygen species mediates ATP release from exposed cells, stimulating activation of the inflammasome in local DCs (Schroder and Tschopp, 2010). The recent advent of ipilimumab in the armamentarium for melanoma treatment finally fulfilled the long-cherished hope for a successful immunotherapy to treat this tumor (Hodi et al., 2010). The immunogenicity of melanoma has been deduced from T cell–mediated spontaneous regressions of primary tumors and the occurrence of melanoma-associated hypopigmentations (Becker et al., 1999; thor Straten et al., 1996). In this regard, the present report by van den Boorn et al. not only provides the modus operandi for the hypopigmenting agent monobenzone but also creates the opportunity for an innovative, easy-to-use immunotherapy for melanoma. Indeed, the same researchers recently reported that monobenzone cream combined with the immunostimulatory adjuvans CpG and imiquimod synergistically induce potent melanoma antigen-specific immunity and tumor eradication in a murine model of melanoma (van den Boorn et al., 2010). Contact-sensitizing compounds generating haptens such as
Clinical Implications • Monobenzone precipitates the development of cellular immunity against melanocytes. • Current research is directed toward the hypothesis that monobenzone will precipitate the development of useful anti-melanoma cellular immunity in similar fashon. • The search for more effective treatments for melanoma has received new impetus.
1186 Journal of Investigative Dermatology (2011), Volume 131
commentary
dinitrochlorobenzene have been used for melanoma therapy in both preclinical and clinical studies (Terheyden et al., 2007; Wack et al., 2002). However, as elegantly demonstrated by van den Boorn et al. (2011, this issue), monobenzone is more specific than dinitrochlorobenzene because it is active only in pigmented cells. Moreover, it is already available as a registered drug with a well-established toxicity profile. It is hoped the present report by van den Boorn et al. will prompt clinical trials testing this concept for immunotherapy of melanoma.
van den Boorn JG, Konijnenberg D, Tjin EP et al. (2010) Effective melanoma immunotherapy in mice by the skin-depigmenting agent monobenzone and the adjuvants imiquimod and CpG. PLoS One 5:e10626 van den Boorn JG, Picavet DI, van Swieten PF et al. (2011) Skin-depigmenting agent monobenzone induces potent T-cell autoimmunity toward pigmented cells by tyrosinase haptenation and melanosome
autophagy. J Invest Dermatol 131:1240–51 Wack C, Kirst A, Becker JC et al. (2002) Chemoimmunotherapy for melanoma with dacarbazine and 2,4-dinitrochlorobenzene elicits a specific T cell-dependent immune response. Cancer Immunol Immunother 51:431–9 Yamaguchi Y, Brenner M, Hearing VJ (2007) The regulation of skin pigmentation. J Biol Chem 282:27557–61
See related article on pg 1291
The authors state no conflict of interest.
Fisetin: A Natural Fist against Melanoma?
References
Jack L. Arbiser1 and David E. Fisher2
CONFLICT OF INTEREST
Becker JC, Guldberg P, Zeuthen J et al. (1999) Accumulation of identical T cells in melanoma and vitiligo-like leukoderma. J Invest Dermatol 113:1033–8 Ezendam J, Vissers I, Bleumink R et al. (2003) Immunomodulatory effects of tetrachlorobenzoquinone, a reactive metabolite of hexachlorobenzene. Chem Res Toxicol 16:688–94 Hartmann A, Bröcker EB, Becker JC (2004) Hypopigmentary skin disorders: current treatment options and future directions. Drugs 64:89–107 Hartmann A, Bedenk C, Keikavoussi P et al. (2008) Vitiligo and melanoma-associated hypopigmentation (MAH): shared and discriminative features. J Dtsch Dermatol Ges 6:1053–9 Hodi FS, O’Day SJ, McDermott DF et al. (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–23 Nordlund JJ, Forget B, Kirkwood J et al. (1985) Dermatitis produced by applications of monobenzone in patients with active vitiligo. Arch Dermatol 121:1141–4 Schroder K, Tschopp J (2010) The inflammasomes. Cell 140:821–32 Solano F, Briganti S, Picardo M et al. (2006) Hypopigmenting agents: an updated review on biological, chemical and clinical aspects. Pigment Cell Res 19:550–71 Terheyden P, Kortum AK, Schulze HJ et al. (2007) Chemoimmunotherapy for cutaneous melanoma with dacarbazine and epifocal contact sensitizers: results of a nationwide survey of the German Dermatologic Co-operative Oncology Group. J Cancer Res Clin Oncol 133:437–44 Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–93 thor Straten P, Becker JC, Seremet T et al. (1996) Clonal T cell responses in tumor infiltrating lymphocytes from both regressive and progressive regions of primary human malignant melanoma. J Clin Invest 98:279–84
Melanoma has now become the subject of targeted therapies, based upon the high prevalence of B-raf mutations in melanoma. However, while initial responses to B-raf inhibitors are impressive, resistance is extremely common, suggesting that melanoma is not addicted to B-raf. In their report, Syed et al. demonstrate that fisetin, a natural product without well established mechanisms, has activity against melanoma. Their report suggests that "nontargeted therapies" need to become part of our armamentarium against melanoma, given that targeted therapies do not target all of the pathways required for melanoma growth. Journal of Investigative Dermatology (2011) 131, 1187–1189. doi:10.1038/jid.2011.39
Several common genetic events in melanoma have been elucidated in recent years. These include oncogenic events, such as the B-raf V600E mutation, amplification of the micro phthalmia transcription factor (MITF), and Nras mutations. Common tumor suppressor events include inactivation of the p16ink4a tumor suppressor gene, often by deletion or hypermethylation, and loss and/or mutation of PTEN, a common event in melanomas with B-raf mutations. Melanomas have been shown to exhibit differing genetic pathways to reach these mutations, depending on their anatomic location. The pathways involve a complex interplay among pigmentation genes such as melanocortin 1 receptor, c-kit, and DNA repair genes.
As our understanding of melanoma genetics has increased, so has our understanding of the signaling pathways relevant to melanoma progression. The current concept of atypical nevi giving rise to a noninvasive melanoma (radial growth phase) and then to an invasive and potentially metastatic phenotype has been confirmed with distinct signaling events, although melanomas may also arise in the absence of preexisting nevi. Atypical nevi are clonal neoplasms with a high frequency of B-raf mutations, but despite the activation of B-raf, they do not exhibit stable activation of MAP kinase (p42/44 ERK). Radial growth melanoma demonstrates high levels of expression of activated MAP kinase, as well as of Id-1 and telomerase. Invasive melanoma
Department of Dermatology, Emory University School of Medicine and Winship Cancer Institute, Atlanta Veterans Administration Hospital, Atlanta, Georgia, USA and 2Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA 1
Correspondence: Jack L. Arbiser, Department of Dermatology, Emory University School of Medicine, WMB 5309, 1639 Pierce Drive, Atlanta, Georgia 30322, USA. E-mail: [email protected]
www.jidonline.org 1187
Copyright of Journal of Investigative Dermatology is the property of Nature Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Mengel-From J, Wong TH, Morling N et al. (2009) Genetic determinants of hair and eye colours in the Scottish and Danish populations. BMC Genet 10:88 Pan H, Wang Z, He B et al. (2010) Identification of a novel mutation in the DSRAD gene in a Chinese family with dyschromatosis symmetrica hereditaria. J Am Acad Dermatol 63:529–30 Shishido E, Kadono S, Manaka I et al. (2001) The mechanism of epidermal hyperpigmentation in dermatofibroma is associated with stem cell factor and hepatocyte growth factor expression. J Invest Dermatol 117:627–33
Stuhrmann M, Hennies HC, Bukhari IA et al. (2008) Dyschromatosis universalis hereditaria: evidence for autosomal recessive inheritance and identification of a new locus on chromosome 12q21–q23. Clin Genet 73:566–72 Wang XP, Liu Y, Wang JM et al. (2010) Two novel splice site mutations of the ADAR1 gene in Chinese families with dyschromatosis symmetrica hereditaria. J Dermatol 37:1051–2 Yamaguchi Y, Hearing VJ (2009) Physiological factors that regulate skin pigmentation. Biofactors 35:193–9
See related article on pg 1240
Breaking Immunological Tolerance to Melanocyte Differentiation Antigens by Hypopigmenting Agents: A New Means for Melanoma Immunotherapy? Jürgen C. Becker1 and David Schrama1 The hypopigmenting agent monobenzone induces inflammatory responses only in pigmented skin as well as depigmentation in areas not directly exposed to the drug. Both observations have been ascribed to the possible induction of adaptive immune responses against melanocytes. In this issue, van den Boorn et al. provide direct evidence confirming this hypothesis. Since the monobenzoneinduced immune responses target melanocyte-differentiation antigens, this report opens the opportunity for a simple and instantaneous deployable immunotherapy of melanoma. Journal of Investigative Dermatology (2011) 131, 1185–1187. doi:10.1038/jid.2011.94
Skin pigmentation depends primarily on the amount and type of melanin synthesized by melanocytes located in the basal layer of the epidermis and its distribution toward the surface of the epidermis (Yamaguchi et al., 2007). Melanin is synthesized within a specialized organelle, the melanosome. The essential enzyme in its synthesis is tyrosinase, a melanosomal membrane glycoprotein that catalyzes the initial and rate-limiting steps of melano
genesis. Ultimately, melanin packed in melanosomes is transferred from the melanocytes to adjacent keratinocytes. Agents to control skin pigmentation are used to address a variety of medical conditions, such as acquired hyperpigmentation and vitiligo (Hartmann et al., 2004). Hypopigmenting agents include hydroquinone or its monobenzyl ether, monobenzone (Solano et al., 2006); the drug Benoquin, manufactured by ICN, contains 20% monobenzone.
Department of General Dermatology, Medical University of Graz, Graz, Austria
1
Correspondence: Jürgen C. Becker, Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, A-8036 Graz, Austria. E-mail: [email protected]
More than 25 years ago, Nordlund et al. reported six patients with spreading vitiligo treated with applications of monobenzone who subsequently developed a vesicular dermatitis (Nordlund et al., 1985). Interestingly, the eruption was restricted to the pigmented areas of the skin. Patch tests applied to pigmented and depigmented skin produced inflammatory responses only within the pigmented areas, indicating that the effect depends on the presence of melanocytes. In this issue, van den Boorn et al. provide an explanation for this puzzling phenomenon (Figure 1). Application of monobenzone induces local depigmentation within 2 weeks, extending within a few months, however, to nonexposed skin sites. This observation indicates that monobenzone-induced depigmentation is not only based on direct effects on melanocytes but also involves a systemic process. Histological examination of biopsies obtained from monobenzone-treated skin revealed CD8+ T-cell infiltrates similar to those observed in spontaneous vitiligo or melanoma-associated hypopigmentation (Hartmann et al., 2008), thereby providing the first clue that the systemic effect probably results from an immunological process. The direct effect of monobenzone is attributed to inhibition of tyrosinase activity. Indeed, van den Boorn et al. (2011, this issue) demonstrated that tyrosinase metabolized monobenzone to 4-benzoxy-1,2-benzoquinone, which in turn inactivates tyrosinase by formation of quinone hapten binding to tyrosinase cysteine residues. Thus, monobenzone exposure reduces pigment-cell melano genesis without exerting selective toxicity. Notably, reactive benzene metabolites such as quinones are effective contact sensitizers, binding to proteins and forming hapten–carrier complexes that trigger hapten-specific immune responses (Ezendam et al., 2003). Consequently, van den Boorn et al. investigated the effects of monobenzone on the immunogenicity of pigmented cells, i.e., melanocytes and melanoma cells. Exposure to monobenzone induced reactive oxygen species exclusively in pigmented cells, associated with an increased release of tyrosinase- and MART-1-containing CD63+ exosomes. Exosomes are known www.jidonline.org 1185
commentary
Melanocyte dendrites
Melanin
Melanosome
Autophagosome Quinone hapten
Tyr
CD63 Release Tyrosine/ MHC class II complex
PIGMENTED CELL
Lysosomal degradation
O
EXOSOME
Reactive oxygen species ⋅OH
Monobenzone
Exosome endocytosis
O 2–⋅ H2O2
OH
Peptide/ MHC class I Tyrosinase
ATP release
H 2N O
O P O P O P O O
Ub Ub Ub
–
O
–
O
N
N
O
O
–
–
N
N
Adenosine triphosphate
O
IMMATURE DENDRITIC CELL
OH OH
NALP3 inflammasome Tyrosine/ MHC class I complex
Pigmented cellreactive CD8+ T-cell response
CD8+ T CELL
MATURE DENDRITIC CELL
Figure 1. Different effects of monobenzone treatment on pigmented cells. Tyrosinase (Tyr.), the rate limiting enzyme in the synthesis of melanin in melanosomes, catalyzes metabolite formation of monobenzone. Quinone haptens derived from the metabolite 4-benzoxy-1,2-benzoquinone bind to tyrosinase cysteine residues which leads to reduced melanin synthesis (upper left corner). In addition, augmented ubiquitination (Ub) of tyrosinase protein by monobenzone exposure enhances the presentation of this enzyme by MHC class I (lower left corner). Monobenzone induces reactive oxygen species (ROS) exclusively in pigmented cells. These ROS provoke the increased release of tyrosinase and Mart-1 containing exosomes and adenosine triphosphate (ATP) as well as melanosome autophagy. The autophagocytic response targets melanosomal tyrosinase protein via lysosomal degradation to MHC class‑II compartments (upper right). Immature dendritic cells will be activated upon endocytosis of quinone-haptenated tyrosinase containing exosomes triggering the NALP3 inflammasome. In addition, ATP released from monobenzone exposed cells will stimulate activation of the inflammasome (lower right). These activated and pigmented cell antigen presenting dendritic cells are then capable of inducing a specific immune response (lower middle). MHC, major histocompatibility complex.
to induce specific immunity (Thery et al., 2009). Moreover, monobenzone also affects antigen processing in pigmented cells by (i) induction of polyubiquit ination of tyrosinase, thereby enhancing its presentation in the major histo compatibility complex class I pathway, and (ii) formation of melanin-containing autophagosomes and autolysosomes. This autophagocytic response was found to target melanosomal tyrosinase protein via lysosomal degradation to major histocompatibility complex class II compartments. The impact of these monobenzoneinduced processes on the induction of cellular immune responses was confirmed by a series of cross-presentation experiments using immature human dendritic cells (DCs) and autologous naive T cells. These experiments demonstrated
that, in contrast to unexposed melanoma cells, intact monobenzone-exposed melanoma cells activated DCs that had taken up exosomes from these cells. Subsequently, these DCs, cultivated with lymphocytes from healthy human donors, induced a robust melanomareactive CD8+ T-cell response within 7 days in vitro. Notably, the induced
T-cell response was not restricted to monobenzone-treated melanoma cells (i.e., specific for epitopes linked to quinone hapten) because unexposed melanoma cells were recognized as well. However, the increased exosome secretion alone cannot account for the observed DC activation by monobenzone-exposed melanoma cells. Thus, it is important to note that monobenzoneexposed pigmented cells may activate DCs in two ways: (i) DC uptake of quinone-haptenated tyrosinase-containing exosomes augments DC activation via additional triggering of the NALP3 inflammasome and (ii) the generation of reactive oxygen species mediates ATP release from exposed cells, stimulating activation of the inflammasome in local DCs (Schroder and Tschopp, 2010). The recent advent of ipilimumab in the armamentarium for melanoma treatment finally fulfilled the long-cherished hope for a successful immunotherapy to treat this tumor (Hodi et al., 2010). The immunogenicity of melanoma has been deduced from T cell–mediated spontaneous regressions of primary tumors and the occurrence of melanoma-associated hypopigmentations (Becker et al., 1999; thor Straten et al., 1996). In this regard, the present report by van den Boorn et al. not only provides the modus operandi for the hypopigmenting agent monobenzone but also creates the opportunity for an innovative, easy-to-use immunotherapy for melanoma. Indeed, the same researchers recently reported that monobenzone cream combined with the immunostimulatory adjuvans CpG and imiquimod synergistically induce potent melanoma antigen-specific immunity and tumor eradication in a murine model of melanoma (van den Boorn et al., 2010). Contact-sensitizing compounds generating haptens such as
Clinical Implications • Monobenzone precipitates the development of cellular immunity against melanocytes. • Current research is directed toward the hypothesis that monobenzone will precipitate the development of useful anti-melanoma cellular immunity in similar fashon. • The search for more effective treatments for melanoma has received new impetus.
1186 Journal of Investigative Dermatology (2011), Volume 131
commentary
dinitrochlorobenzene have been used for melanoma therapy in both preclinical and clinical studies (Terheyden et al., 2007; Wack et al., 2002). However, as elegantly demonstrated by van den Boorn et al. (2011, this issue), monobenzone is more specific than dinitrochlorobenzene because it is active only in pigmented cells. Moreover, it is already available as a registered drug with a well-established toxicity profile. It is hoped the present report by van den Boorn et al. will prompt clinical trials testing this concept for immunotherapy of melanoma.
van den Boorn JG, Konijnenberg D, Tjin EP et al. (2010) Effective melanoma immunotherapy in mice by the skin-depigmenting agent monobenzone and the adjuvants imiquimod and CpG. PLoS One 5:e10626 van den Boorn JG, Picavet DI, van Swieten PF et al. (2011) Skin-depigmenting agent monobenzone induces potent T-cell autoimmunity toward pigmented cells by tyrosinase haptenation and melanosome
autophagy. J Invest Dermatol 131:1240–51 Wack C, Kirst A, Becker JC et al. (2002) Chemoimmunotherapy for melanoma with dacarbazine and 2,4-dinitrochlorobenzene elicits a specific T cell-dependent immune response. Cancer Immunol Immunother 51:431–9 Yamaguchi Y, Brenner M, Hearing VJ (2007) The regulation of skin pigmentation. J Biol Chem 282:27557–61
See related article on pg 1291
The authors state no conflict of interest.
Fisetin: A Natural Fist against Melanoma?
References
Jack L. Arbiser1 and David E. Fisher2
CONFLICT OF INTEREST
Becker JC, Guldberg P, Zeuthen J et al. (1999) Accumulation of identical T cells in melanoma and vitiligo-like leukoderma. J Invest Dermatol 113:1033–8 Ezendam J, Vissers I, Bleumink R et al. (2003) Immunomodulatory effects of tetrachlorobenzoquinone, a reactive metabolite of hexachlorobenzene. Chem Res Toxicol 16:688–94 Hartmann A, Bröcker EB, Becker JC (2004) Hypopigmentary skin disorders: current treatment options and future directions. Drugs 64:89–107 Hartmann A, Bedenk C, Keikavoussi P et al. (2008) Vitiligo and melanoma-associated hypopigmentation (MAH): shared and discriminative features. J Dtsch Dermatol Ges 6:1053–9 Hodi FS, O’Day SJ, McDermott DF et al. (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–23 Nordlund JJ, Forget B, Kirkwood J et al. (1985) Dermatitis produced by applications of monobenzone in patients with active vitiligo. Arch Dermatol 121:1141–4 Schroder K, Tschopp J (2010) The inflammasomes. Cell 140:821–32 Solano F, Briganti S, Picardo M et al. (2006) Hypopigmenting agents: an updated review on biological, chemical and clinical aspects. Pigment Cell Res 19:550–71 Terheyden P, Kortum AK, Schulze HJ et al. (2007) Chemoimmunotherapy for cutaneous melanoma with dacarbazine and epifocal contact sensitizers: results of a nationwide survey of the German Dermatologic Co-operative Oncology Group. J Cancer Res Clin Oncol 133:437–44 Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–93 thor Straten P, Becker JC, Seremet T et al. (1996) Clonal T cell responses in tumor infiltrating lymphocytes from both regressive and progressive regions of primary human malignant melanoma. J Clin Invest 98:279–84
Melanoma has now become the subject of targeted therapies, based upon the high prevalence of B-raf mutations in melanoma. However, while initial responses to B-raf inhibitors are impressive, resistance is extremely common, suggesting that melanoma is not addicted to B-raf. In their report, Syed et al. demonstrate that fisetin, a natural product without well established mechanisms, has activity against melanoma. Their report suggests that "nontargeted therapies" need to become part of our armamentarium against melanoma, given that targeted therapies do not target all of the pathways required for melanoma growth. Journal of Investigative Dermatology (2011) 131, 1187–1189. doi:10.1038/jid.2011.39
Several common genetic events in melanoma have been elucidated in recent years. These include oncogenic events, such as the B-raf V600E mutation, amplification of the micro phthalmia transcription factor (MITF), and Nras mutations. Common tumor suppressor events include inactivation of the p16ink4a tumor suppressor gene, often by deletion or hypermethylation, and loss and/or mutation of PTEN, a common event in melanomas with B-raf mutations. Melanomas have been shown to exhibit differing genetic pathways to reach these mutations, depending on their anatomic location. The pathways involve a complex interplay among pigmentation genes such as melanocortin 1 receptor, c-kit, and DNA repair genes.
As our understanding of melanoma genetics has increased, so has our understanding of the signaling pathways relevant to melanoma progression. The current concept of atypical nevi giving rise to a noninvasive melanoma (radial growth phase) and then to an invasive and potentially metastatic phenotype has been confirmed with distinct signaling events, although melanomas may also arise in the absence of preexisting nevi. Atypical nevi are clonal neoplasms with a high frequency of B-raf mutations, but despite the activation of B-raf, they do not exhibit stable activation of MAP kinase (p42/44 ERK). Radial growth melanoma demonstrates high levels of expression of activated MAP kinase, as well as of Id-1 and telomerase. Invasive melanoma
Department of Dermatology, Emory University School of Medicine and Winship Cancer Institute, Atlanta Veterans Administration Hospital, Atlanta, Georgia, USA and 2Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA 1
Correspondence: Jack L. Arbiser, Department of Dermatology, Emory University School of Medicine, WMB 5309, 1639 Pierce Drive, Atlanta, Georgia 30322, USA. E-mail: [email protected]
www.jidonline.org 1187
Copyright of Journal of Investigative Dermatology is the property of Nature Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.