Mechanisms of local immunosuppression in cutaneous melanoma.
Marta E Polak,Nicola J Borthwick,Francis G Gabriel,Penny Johnson,Bernard Higgins,Jeremy Hurren,D McCormick,Martine J. Jager,Ian A. Cree +8 more
TLDR
This results indicate that tolerogenic DCs and suppressor T lymphocytes are present in melanoma at all stages of disease progression, and suggest that negative SLN contain immunosuppressive cells and cytokines, due to preconditioning by tolerogenicDCs migrating from the primary melanoma site to the SLN.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, TGFβ1 and TGFβ2) 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 β receptor 1 (TGFβR1), and are therefore susceptible to TGFβ1 and TGFβ2 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, TGFβ2 is likely to render peripheral DCs tolerogenic, while in lymph nodes IDO and TGFβ1 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.read more
Citations
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Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4
Rikke B. Holmgaard,Dmitriy Zamarin,David H. Munn,Jedd D. Wolchok,Jedd D. Wolchok,Jedd D. Wolchok,James P. Allison,James P. Allison +7 more
TL;DR: Indoleamine 2,3-dioxygenase suppresses infiltration and accumulation of tumor-reactive T cells in the context of anti–CTLA-4 immunotherapy and attenuates the anti-tumor efficacy.
Journal ArticleDOI
Strategies for use of IL‐10 or its antagonists in human disease
TL;DR: Interleukin‐10 is a cytokine with broad anti‐inflammatory properties by its suppression of both macrophage and dendritic cell function, including antigen‐presenting cell function and the production of proinflammatory cytokines, which shows great potential as adjuvants in preventative or therapeutic vaccines against chronic infection or cancer.
Journal ArticleDOI
Indoleamine 2,3-Dioxygenase Expression in Human Cancers: Clinical and Immunologic Perspectives
TL;DR: In this article, the authors reviewed several studies that correlate IDO expression in human cancer samples and tumor-draining lymph nodes, with relevant clinical or immunologic parameters, and concluded that increased IDOexpression correlates with diverse tumor progression parameters and shorter patient survival.
Indoleamine2,3-DioxygenaseExpressioninHumanCancers: Clinical and Immunologic Perspectives
TL;DR: The impact of IDO on different immune cell infiltration leads to the conclusion that IDO negatively regulates the recruitment of antitumor immune cells and increased IDO expression correlates with diverse tumor progression parameters and shorter patient survival.
Journal ArticleDOI
Current concepts of metastasis in melanoma
Blazej Zbytek,J. Andrew Carlson,Jacqueline Granese,Jeffrey S. Ross,Martin C. Mihm,Andrzej Slominski +5 more
TL;DR: It is thought that one of the reasons why melanoma cells are especially resistant to killing is the fact that melanocytes are resistant to such noxious factors as ultraviolet light and reactive oxygen species.
References
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Journal ArticleDOI
IDO expression by dendritic cells: tolerance and tryptophan catabolism.
Andrew L. Mellor,David H. Munn +1 more
TL;DR: This review summarizes key recent developments and proposes a unifying model for the role of IDO in tolerance induction, including studies of mammalian pregnancy, tumour resistance, chronic infections and autoimmune diseases.
Journal ArticleDOI
Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity?
Manfred B. Lutz,Gerold Schuler +1 more
TL;DR: Closer inspection reveals that tolerance is observed when partial- or semi-maturation of DCs occurs, whereas only full DC maturation is immunogenic, and the decisive immunogenic signal seems to be the release of proinflammatory cytokines from the DCs.
Journal ArticleDOI
Tumor cells convert immature myeloid dendritic cells into TGF-β–secreting cells inducing CD4+CD25+ regulatory T cell proliferation
François Ghiringhelli,Pierre Emmanuel Puig,Stephan Roux,Arnaud Parcellier,Elise Schmitt,Eric Solary,Guido Kroemer,François Martin,Bruno Chauffert,Laurence Zitvogel +9 more
TL;DR: Tumor cells are necessary and sufficient to convert DCs into regulatory cells that secrete bioactive TGF-β and stimulate T reg cell proliferation, and tumor expansion can stimulate Treg cells via a specific DC subset.
Journal ArticleDOI
Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells.
Gerald Brandacher,Alexander Perathoner,Ruth Ladurner,Ruth Ladurner,Stefan Schneeberger,Peter Obrist,Christiana Winkler,Ernst R. Werner,Gabriele Werner-Felmayer,Helmut Weiss,Georg Göbel,Raimund Margreiter,Alfred Königsrainer,Alfred Königsrainer,Dietmar Fuchs,Albert Amberger +15 more
TL;DR: IDO-high expression by colorectal tumor cells enables certain cancer subsets to initially avoid immune attack and defeat the invasion of T cells via local tryptophan depletion and the production of proapoptotic tryPTophan catabolites.
Journal ArticleDOI
Measurement of gene expression in archival paraffin-embedded tissues: development and performance of a 92-gene reverse transcriptase-polymerase chain reaction assay.
Maureen T. Cronin,Mylan Pho,Debjani Dutta,James C. Stephans,Steven Shak,Michael C. Kiefer,Jose M. Esteban,Joffre B. Baker +7 more
TL;DR: It is shown that the extent of fragmentation of extracted FPE tissue RNA significantly increases with archive storage time, and this findings support the development of RT-PCR analysis of F PE tissue RNA as a platform for multianalyte clinical diagnostic tests.
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