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Oral cancer treatment and immune targets – A role for dendritic cells?
Journal of Cranio-Maxillo-Facial Surgery 40 (2012) 103e104
Contents lists available at ScienceDirect
Journal of Cranio-Maxillo-Facial Surgery journal homepage: www.jcmfs.com
Case report
Oral cancer treatment and immune targets e A role for dendritic cells? Hans-Robert Metelmann*, Peter Hyckel, Fred Podmelle Department of Oral and Maxillofacial Surgery/Plastic Surgery (Head: Prof. Hans-Robert Metelmann), Greifswald University, Ferdinand-Sauerbruch-Str. Bettenhaus I, D-17475 Greifswald, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Paper received 3 December 2010 Accepted 1 March 2011
Treating a patient suffering from an advanced oral cavity carcinoma by peritumoural injections of mistletoe preparation resulted in a surprising partial response. At the same time an early metastasis, located at the kidney, however remained unaffected. The main difference in treatment being peritumoural versus systematic application supports the hypothesis of immune surveillance. The impact of mistletoe extract in direct contact with the tumour tissue might be explained as activation of macrophage polarization followed by induced cytotoxicity. No direct contact is resulting in no direct macrophage activation. At present there is no clinical trial outlined to test this hypothesis, but as a beginning we would like to encourage submission of case reports with similar clinical experience. Ó 2011 European Association for Cranio-Maxillo-Facial Surgery.
Keywords: Advanced oral cavity carcinoma Peritumoural injections of mistletoe preparation Activation of macrophage polarization Partial response to clinical treatment
1. Introduction The effects of mistletoe therapy in oncology have to be considered very cautiously (Klopp et al., 2005). There are some data showing the influence of complementary Viscum album administration on the microcirculation and immune systems of oropharyngeal carcinoma patients treated with radiation and chemotherapy (Horneber et al., 2008). However, from a clinical point of view there is no case report in the literature describing at least a slowing effect of mistletoe injections on an advanced oral cavity carcinoma with no other tumour treatment at all. 2. Case report A 66-year-old Caucasian man presented in May 2007 with an exophytic tumour at the base of the tongue with palpable and massively enlarged lymph nodes on both sides of the neck cT4a-b, cN2b, cM0. Histological examination of the tumour area revealed a poorly differentiated squamous cell carcinoma with a low tendency to keratosis. The patient refused any kind of surgery or radio therapy fearing the side effects and complications of this kind of treatment, however finally agreed to take a treatment protocol of peritumoural injections of a mistletoe preparation (Abnoba Viscum abietis 0.2 mg) every two weeks. This kind of fourth-line-immune therapy (surgery, radio therapy and cytostatic chemotherapy being the three main lines, however rejected) started in November 2007. * Corresponding author. Tel.: þ49 38 34 86 71 60; fax: þ49 38 34 86 73 16. E-mail address: [email protected] (H.-R. Metelmann).
The tumour of the tongue has stopped growing. MRT-imaging demonstrates lymph node metastasis to show no progression and the primary tumour is becoming smaller. Subsequent histological follow-up of the primary tumour reveals malignant epithelial cells imbedded in major spots of keratinisation and surrounded by a local inflammatory reaction. With the tumour of the tongue still in partial remission the patient presented in June 2009 with a second malignant tumour of the same kind, now located within the right kidney. Retrospective investigation of previous MRT-imaging showed that in May 2007 there was already a tiny irregularity visible at the site. Further treatment follows a protocol of repeated peritumoural injections of mistletoe preparation. The tumour of the tongue by is still under control. The second tumour in the area of the kidney is rapidly growing, limiting the survival of the patient.
3. Discussion From an experimental point of view the different behaviour of the two tumours is provoking an explanation via macrophage activation. The case study impressively supports the hypothesis of immune surveillance (Swann and Smyth, 2007; Reiman et al., 2007). The cytostatic effect of mistletoe lectin in cultivated oral cavity carcinoma stem cells is well documented (Metelmann et al., 1992). Furthermore, mistletoe leads to an up-regulation of IL12 and TNF alpha in macrophages (Heinzerling et al., 2006). IL12 and TNF alpha expression is characteristic for the classically activated or M1 tumour-related macrophage (TAM) which is related to tumour rejection (Ostrand-Rosenberg, 2008; Mantovani and Sica, 2010;
1010-5182/$ e see front matter Ó 2011 European Association for Cranio-Maxillo-Facial Surgery. doi:10.1016/j.jcms.2011.03.009
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H.-R. Metelmann et al. / Journal of Cranio-Maxillo-Facial Surgery 40 (2012) 103e104
DeNardo et al., 2010). In contrast, tumour progression (as in the case presented) is associated with the occurrence of M2 macrophages (Braun et al., 2003; Elluru et al., 2008). The immunsuppressive reactivity of M2 macrophages corresponds to a reduced response to mitogens, e.g. PHA (Hyckel et al., 1985).
4. Conclusion In conclusion, the following hypothesis of the therapeutic effect of mistletoe is proposed: by peritumoral mistletoe application a switch from tolerogen M2 to proinflammatory M1 macrophages is induced (Hajtó et al., 2009). As a result of M1 activation, there is a maturation of dendritic cells leading to tumour antigen presentation and subsequently to a suppression of tumour growth and metastasis. The impact of mistletoe extracts injected in the periphery of the tumour might be explained by activation of macrophage polarization (M1). Maturation of dendritic cells is going along with an induced cytotoxicity and the performance of antigen presenting cells. Conflict of interest statement There is no conflict of the interest due to the case report. References Braun JM, Blackwell CC, Weir DM, Beuth J: Cytokine release of whole blood from adult female donors challenged with mistletoe lectin-1 standardised mistletoe extract and E. coli endotoxin or phytohaemagglutinin (PHA). Anticancer Res 23(2B): 1349e1352, 2003
DeNardo DG, Andreu P, Coussens LM: Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev 29(2): 309e316, 2010 Elluru SR, van Huyen JP, Delignat S, Kazatchkine MD, Friboulet A, Kaveri SV, et al: Induction of maturation and activation of human dendritic cells: a mechanism underlying the beneficial effect of Viscum album as complimentary therapy in cancer. BMC Cancer 8: 161, 2008 Hajtó T, Fodor K, Perjési P, Németh P: Difficulties and perspectives of immunomodulatory therapy with mistletoe lectins and standardized mistletoe extracts in evidence-based medicine. Evid Based Complement Alternat Med Epub 2009 Nov 25 Heinzerling L, von Baehr V, Liebenthal C, von Baehr R, Volk HD: Immunologic effector mechanisms of a standardized mistletoe extract on the function of human monocytes and lymphocytes in vitro, ex vivo, and in vivo. J Clin Immuno 26(4): 347e359, 2006 Horneber MA, Bueschel G, Huber R, Linde K, Rostock M: Mistletoe therapy in oncology. Cochrane Database Syst Rev (2):CD003297 2008 Hyckel P, Metzner G, Müller P, Quade R: Prognostic relevance of histologic and immunologic parameters as a contribution to the data on individualized treatment plans for carcinoma of the mouth. Dtsch Z Mund Kiefer Gesichtschir 9(6): 475e480, 1985 Klopp R, Schmidt W, Werner E, Werner M, Niemer W, Beuth J: Influence of complementary Viscum album administration on microcirculation and immune system of ear, nose and throat carcinoma patients treated with radiation and chemotherapy. Anticancer Res 25(1B): 601e610, 2005 Mantovani A, Sica A: Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22(2): 231e237, 2010 Metelmann HR, Wartenberg E, Kindermann H, Platz H, Scheffler A: Direct antineoplastic activity of different mistletoe preparations against oral cancer cells in vitro. Proc AACR Clinical Investigations 33: 224, 1992 Swann JB, Smyth MJJ: Immune surveillance of tumors. J Clin Invest 117(5): 1137e1146, 2007 Ostrand-Rosenberg S: Immune surveillance: a balance between protumor and antitumor immunity. Curr Opin Genet Dev 18(1): 8e11, 2008 Reiman JM, Kmieciak M, Manjili MH, Knutson K: Tumor immunoediting and immunosculpting pathways to cancer progression. Semin Cancer Biol 17(4): 275e287, Epub June 26 2007
Contents lists available at ScienceDirect
Journal of Cranio-Maxillo-Facial Surgery journal homepage: www.jcmfs.com
Case report
Oral cancer treatment and immune targets e A role for dendritic cells? Hans-Robert Metelmann*, Peter Hyckel, Fred Podmelle Department of Oral and Maxillofacial Surgery/Plastic Surgery (Head: Prof. Hans-Robert Metelmann), Greifswald University, Ferdinand-Sauerbruch-Str. Bettenhaus I, D-17475 Greifswald, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Paper received 3 December 2010 Accepted 1 March 2011
Treating a patient suffering from an advanced oral cavity carcinoma by peritumoural injections of mistletoe preparation resulted in a surprising partial response. At the same time an early metastasis, located at the kidney, however remained unaffected. The main difference in treatment being peritumoural versus systematic application supports the hypothesis of immune surveillance. The impact of mistletoe extract in direct contact with the tumour tissue might be explained as activation of macrophage polarization followed by induced cytotoxicity. No direct contact is resulting in no direct macrophage activation. At present there is no clinical trial outlined to test this hypothesis, but as a beginning we would like to encourage submission of case reports with similar clinical experience. Ó 2011 European Association for Cranio-Maxillo-Facial Surgery.
Keywords: Advanced oral cavity carcinoma Peritumoural injections of mistletoe preparation Activation of macrophage polarization Partial response to clinical treatment
1. Introduction The effects of mistletoe therapy in oncology have to be considered very cautiously (Klopp et al., 2005). There are some data showing the influence of complementary Viscum album administration on the microcirculation and immune systems of oropharyngeal carcinoma patients treated with radiation and chemotherapy (Horneber et al., 2008). However, from a clinical point of view there is no case report in the literature describing at least a slowing effect of mistletoe injections on an advanced oral cavity carcinoma with no other tumour treatment at all. 2. Case report A 66-year-old Caucasian man presented in May 2007 with an exophytic tumour at the base of the tongue with palpable and massively enlarged lymph nodes on both sides of the neck cT4a-b, cN2b, cM0. Histological examination of the tumour area revealed a poorly differentiated squamous cell carcinoma with a low tendency to keratosis. The patient refused any kind of surgery or radio therapy fearing the side effects and complications of this kind of treatment, however finally agreed to take a treatment protocol of peritumoural injections of a mistletoe preparation (Abnoba Viscum abietis 0.2 mg) every two weeks. This kind of fourth-line-immune therapy (surgery, radio therapy and cytostatic chemotherapy being the three main lines, however rejected) started in November 2007. * Corresponding author. Tel.: þ49 38 34 86 71 60; fax: þ49 38 34 86 73 16. E-mail address: [email protected] (H.-R. Metelmann).
The tumour of the tongue has stopped growing. MRT-imaging demonstrates lymph node metastasis to show no progression and the primary tumour is becoming smaller. Subsequent histological follow-up of the primary tumour reveals malignant epithelial cells imbedded in major spots of keratinisation and surrounded by a local inflammatory reaction. With the tumour of the tongue still in partial remission the patient presented in June 2009 with a second malignant tumour of the same kind, now located within the right kidney. Retrospective investigation of previous MRT-imaging showed that in May 2007 there was already a tiny irregularity visible at the site. Further treatment follows a protocol of repeated peritumoural injections of mistletoe preparation. The tumour of the tongue by is still under control. The second tumour in the area of the kidney is rapidly growing, limiting the survival of the patient.
3. Discussion From an experimental point of view the different behaviour of the two tumours is provoking an explanation via macrophage activation. The case study impressively supports the hypothesis of immune surveillance (Swann and Smyth, 2007; Reiman et al., 2007). The cytostatic effect of mistletoe lectin in cultivated oral cavity carcinoma stem cells is well documented (Metelmann et al., 1992). Furthermore, mistletoe leads to an up-regulation of IL12 and TNF alpha in macrophages (Heinzerling et al., 2006). IL12 and TNF alpha expression is characteristic for the classically activated or M1 tumour-related macrophage (TAM) which is related to tumour rejection (Ostrand-Rosenberg, 2008; Mantovani and Sica, 2010;
1010-5182/$ e see front matter Ó 2011 European Association for Cranio-Maxillo-Facial Surgery. doi:10.1016/j.jcms.2011.03.009
104
H.-R. Metelmann et al. / Journal of Cranio-Maxillo-Facial Surgery 40 (2012) 103e104
DeNardo et al., 2010). In contrast, tumour progression (as in the case presented) is associated with the occurrence of M2 macrophages (Braun et al., 2003; Elluru et al., 2008). The immunsuppressive reactivity of M2 macrophages corresponds to a reduced response to mitogens, e.g. PHA (Hyckel et al., 1985).
4. Conclusion In conclusion, the following hypothesis of the therapeutic effect of mistletoe is proposed: by peritumoral mistletoe application a switch from tolerogen M2 to proinflammatory M1 macrophages is induced (Hajtó et al., 2009). As a result of M1 activation, there is a maturation of dendritic cells leading to tumour antigen presentation and subsequently to a suppression of tumour growth and metastasis. The impact of mistletoe extracts injected in the periphery of the tumour might be explained by activation of macrophage polarization (M1). Maturation of dendritic cells is going along with an induced cytotoxicity and the performance of antigen presenting cells. Conflict of interest statement There is no conflict of the interest due to the case report. References Braun JM, Blackwell CC, Weir DM, Beuth J: Cytokine release of whole blood from adult female donors challenged with mistletoe lectin-1 standardised mistletoe extract and E. coli endotoxin or phytohaemagglutinin (PHA). Anticancer Res 23(2B): 1349e1352, 2003
DeNardo DG, Andreu P, Coussens LM: Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev 29(2): 309e316, 2010 Elluru SR, van Huyen JP, Delignat S, Kazatchkine MD, Friboulet A, Kaveri SV, et al: Induction of maturation and activation of human dendritic cells: a mechanism underlying the beneficial effect of Viscum album as complimentary therapy in cancer. BMC Cancer 8: 161, 2008 Hajtó T, Fodor K, Perjési P, Németh P: Difficulties and perspectives of immunomodulatory therapy with mistletoe lectins and standardized mistletoe extracts in evidence-based medicine. Evid Based Complement Alternat Med Epub 2009 Nov 25 Heinzerling L, von Baehr V, Liebenthal C, von Baehr R, Volk HD: Immunologic effector mechanisms of a standardized mistletoe extract on the function of human monocytes and lymphocytes in vitro, ex vivo, and in vivo. J Clin Immuno 26(4): 347e359, 2006 Horneber MA, Bueschel G, Huber R, Linde K, Rostock M: Mistletoe therapy in oncology. Cochrane Database Syst Rev (2):CD003297 2008 Hyckel P, Metzner G, Müller P, Quade R: Prognostic relevance of histologic and immunologic parameters as a contribution to the data on individualized treatment plans for carcinoma of the mouth. Dtsch Z Mund Kiefer Gesichtschir 9(6): 475e480, 1985 Klopp R, Schmidt W, Werner E, Werner M, Niemer W, Beuth J: Influence of complementary Viscum album administration on microcirculation and immune system of ear, nose and throat carcinoma patients treated with radiation and chemotherapy. Anticancer Res 25(1B): 601e610, 2005 Mantovani A, Sica A: Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22(2): 231e237, 2010 Metelmann HR, Wartenberg E, Kindermann H, Platz H, Scheffler A: Direct antineoplastic activity of different mistletoe preparations against oral cancer cells in vitro. Proc AACR Clinical Investigations 33: 224, 1992 Swann JB, Smyth MJJ: Immune surveillance of tumors. J Clin Invest 117(5): 1137e1146, 2007 Ostrand-Rosenberg S: Immune surveillance: a balance between protumor and antitumor immunity. Curr Opin Genet Dev 18(1): 8e11, 2008 Reiman JM, Kmieciak M, Manjili MH, Knutson K: Tumor immunoediting and immunosculpting pathways to cancer progression. Semin Cancer Biol 17(4): 275e287, Epub June 26 2007