title: Mechanisms of local immunosuppression in cutaneous melanoma.
abstract: Cutaneous melanoma is highly immunogenic, yet primary melanomas and metastases develop successfully in otherwise immunocompetent patients. To investigate the local immunosuppressive microenvironment, we examined the presence of suppressor T lymphocytes and tolerising dendritic cells (DCs), the expression of immunosuppressive cytokines (IL-10, TGFbeta1 and TGFbeta2) and the enzyme indoleamine 2,3-dioxygenase (IDO) using qRT-PCR and immunohistochemistry in primary skin melanomas, negative and positive sentinel lymph nodes (SLN), and lymph nodes with advanced metastases. Our results indicate that tolerogenic DCs and suppressor T lymphocytes are present in melanoma at all stages of disease progression. They express transforming growth factor beta receptor 1 (TGFbetaR1), and are therefore susceptible to TGFbeta1 and TGFbeta2 specifically expressed by primary melanoma. We found that expression of IDO and interleukin 10 (IL-10) increased with melanoma progression, with the highest concentration in positive SLN. We suggest that negative SLN contain immunosuppressive cells and cytokines, due to preconditioning by tolerogenic DCs migrating from the primary melanoma site to the SLN. In primary melanoma, TGFbeta2 is likely to render peripheral DCs tolerogenic, while in lymph nodes IDO and TGFbeta1 may have a major effect. This mechanism of tumour-associated immunosuppression may inhibit the immune response to the tumour and may explain the discrepancy between the induction of systemic immunity by anti-melanoma vaccines and their poor performance in the clinic.
authors.affiliation: Translational Oncology Research Centre, Department of Surgery and Histopathology, Queen Alexandra Hospital, Southwick Hill, Portsmouth PO6 3LY, UK. marta.pola@porthosp.nhs.uk
authors.forename: M E
authors.initials: ME
authors.lastname: Polak
authors.forename: N J
authors.initials: NJ
authors.lastname: Borthwick
authors.forename: F G
authors.initials: FG
authors.lastname: Gabriel
authors.forename: P
authors.initials: P
authors.lastname: Johnson
authors.forename: B
authors.initials: B
authors.lastname: Higgins
authors.forename: J
authors.initials: J
authors.lastname: Hurren
authors.forename: D
authors.initials: D
authors.lastname: McCormick
authors.forename: M J
authors.initials: MJ
authors.lastname: Jager
authors.forename: I A
authors.initials: IA
authors.lastname: Cree
mesh_terms: D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology; D008207:Lymphatic Metastasis / Q000276:immunology; D008545:Melanoma / Q000276:immunology*; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D012878:Skin Neoplasms / Q000276:immunology*
chemical_list: D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012334:RNA, Neoplasm