CLINICAL REPORT
483 Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV
Clinical, Genetic and Innate Immunity Characteristics of Melanoma in Organ Transplant Recipients
Anabelle BROCARD 1, 2, Anne-Chantal KNOL 2, Céline BOSSARD 3, Marc Guillaume DENIS 2, 4, Gaëlle QUÉREUX 1, 2, Mélanie SAINT-JEAN 1, 2, Lucie PEUVREL 1, 2, Amir KHAMMARI 1, 2, Gilles BLANCHO 5, Jacques DANTAL 5 and Brigitte DRÉNO 1, 2
1
Department of Dermatology, Nantes University Hospital, 2 CIC, INSERM 892, 3 Service d’ Anatomie et Cytologie Pathologiques, 4 Laboratoire de biochimie plateforme de génétique des tumeurs, and 5 Institut Urologie-Néphrologie, Nantes University Hospital, Nantes, France
The aims of this study were to determine the clinical and histological characteristics of melanoma in transplant recipients, the mutation profile( BRAF, NRAS and c-KIT genes), and the immune tolerance of the tumour microenvironment by immunohistochemical study of the expression of indoleamine 2,3-dioxygenase( IDO), PD1, PD-L1, CD8 and FoxP3. The study population comprised patients who had undergone a renal transplant in Nantes University Hospital who developed post-transplantation melanoma. Twenty cases of melanoma out of 4,663 transplant recipients were studied. The results differed from the usual data with respect to melanoma site: 40 % were located on the face and were of the malignant lentigo type. The mutation profile was concordant with that of the immunocompetent population. IDO was expressed in all the sections tested, while CD8, FoxP3, PD1 and PD-L1 were poorly expressed. This reflected a highly immunodepressed tumour environment, raising the question of the inductive role of IDO on tumour immune tolerance in patients presenting with long-term immunodepression.
Key words: melanoma; organ transplant recipients; IDO; BRAF mutation; malignant lentigo.
Accepted Nov 8, 2016; Epub ahead of print Nov 10, 2016 Acta Derm Venereol 2017; 97: 483 – 488.
Corr: Brigitte Dréno, Department of Dermatology, Nantes University Hospital, 1 place Alexis Ricordeau, FR-44093 Nantes Cedex, France. E-mail: Brigitte. dreno @ wanadoo. fr
Organ transplant recipients are increasing in number and their long-term survival is improving( 1). The patients require long-term immunosuppressant treatment( 2). The prolonged modification of the immune system of organ transplant recipients is associated with a risk of developing various forms of cancer, mainly skin cancer( 3, 4). The risk of developing post-transplantation melanoma is 2- to 3-fold higher than that of the overall population, with a poorer outcome in transplant recipients( 5 – 7). The literature on melanoma in that population is not abundant; few data are available with regard to translational research on melanoma in organ transplant recipients( 8). This study had 2 objectives: a clinical objective consisting in determining the main clinical and histological characteristics of melanoma in transplant recipients. The second objective was to examine histological specimens of primary melanoma emerging post-kidney transplantation in patients at Nantes University Hospital, to determine the mutational profile( BRAF, NRAS, c-KIT genes) of the melanoma and the degree of immune tolerance of the tumour microenvironment by studying the markers of innate immunity: indoleamine 2,3-dioxygenase( IDO), programmed cell death 1( PD1), programmed cell death ligand 1( PD-L1), CD8 and FoxP3. The choice of innate marker has been performed to evaluate the immunosuppressive state of the microenvironment of melanoma.
IDO expression causes infiltrating effector T cells to arrest in G1, become anergic, and die by apoptosis. In addition, toxic metabolites of tryptophan can directly suppress tumour-infiltrating T cells. Finally, IDO-expressing dendritic cells can induce systemic anergy by expanding proliferation of T regulatory cells. PD-1 is an immune checkpoint protein of T lymphocytes, whose link with its ligand PD-L1 expressed by melanoma cells and dendritic cells, induces inhibition of activation of T lymphocytes. FoxP3 is a marker of T reg cells inhibiting the activation between T lymphocytes and melanoma cells and CD4 are cytotoxic T cells directed against melanoma cells
Our hypothesis was that long-term immunosuppression in such patients could induce a decrease in innate immunity, for which one of the consequences was, in particular, an increase in the prevalence of melanoma in that population.
MATERIALS AND METHODS
This retrospective study included all kidney transplant recipients in the Immunology and Nephrology Department of Nantes University Hospital who developed post-transplantation melanoma from 1970 to May 2015. Patients were identified from the dermatological monitoring of transplantation recipients and software for computerized and validated transplantation data( DIVAT)( 9) developed by the Immunology and Nephrology Department. DIVAT is a database that prospectively collects medical information on all adult kidney and / or pancreas transplant recipients, using software that enables data retrieval from the database for epidemiological analysis. For dermatological follow-up, organ transplant recipients are followed either in a dedicated dermatology clinic in Nantes or in outpatient clinic consultations( i. e. open-care practice), in which patients make their own appointment and take charge of their own dermatological monitoring( although they are reminded to do this at each visit); while in the dedicated dermatology clinic, appointments are made for the patients by hospital staff. The choice between open-care practice and the dedicated dermatology clinic is not made by the doctors: all organ transplant recipients are
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2017 Acta Dermato-Venereologica. doi: 10.2340 / 00015555-2568 Acta Derm Venereol 2017; 97: 483 – 488