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Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions

Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNγ secretion by CD8(+) T cells is critical for therapy efficacy having anti-proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFNγ resistance in different melanoma pat...

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Autores principales: Sucker, Antje, Zhao, Fang, Pieper, Natalia, Heeke, Christina, Maltaner, Raffaela, Stadtler, Nadine, Real, Birgit, Bielefeld, Nicola, Howe, Sebastian, Weide, Benjamin, Gutzmer, Ralf, Utikal, Jochen, Loquai, Carmen, Gogas, Helen, Klein-Hitpass, Ludger, Zeschnigk, Michael, Westendorf, Astrid M., Trilling, Mirko, Horn, Susanne, Schilling, Bastian, Schadendorf, Dirk, Griewank, Klaus G., Paschen, Annette
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460020/
https://www.ncbi.nlm.nih.gov/pubmed/28561041
http://dx.doi.org/10.1038/ncomms15440
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author Sucker, Antje
Zhao, Fang
Pieper, Natalia
Heeke, Christina
Maltaner, Raffaela
Stadtler, Nadine
Real, Birgit
Bielefeld, Nicola
Howe, Sebastian
Weide, Benjamin
Gutzmer, Ralf
Utikal, Jochen
Loquai, Carmen
Gogas, Helen
Klein-Hitpass, Ludger
Zeschnigk, Michael
Westendorf, Astrid M.
Trilling, Mirko
Horn, Susanne
Schilling, Bastian
Schadendorf, Dirk
Griewank, Klaus G.
Paschen, Annette
author_facet Sucker, Antje
Zhao, Fang
Pieper, Natalia
Heeke, Christina
Maltaner, Raffaela
Stadtler, Nadine
Real, Birgit
Bielefeld, Nicola
Howe, Sebastian
Weide, Benjamin
Gutzmer, Ralf
Utikal, Jochen
Loquai, Carmen
Gogas, Helen
Klein-Hitpass, Ludger
Zeschnigk, Michael
Westendorf, Astrid M.
Trilling, Mirko
Horn, Susanne
Schilling, Bastian
Schadendorf, Dirk
Griewank, Klaus G.
Paschen, Annette
author_sort Sucker, Antje
collection PubMed
description Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNγ secretion by CD8(+) T cells is critical for therapy efficacy having anti-proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFNγ resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFNγ activity. JAK1/2 mutants further evolve into T-cell-resistant HLA class I-negative lesions with genes involved in antigen presentation silenced and no longer inducible by IFNγ. Allelic JAK1/2 losses predisposing to IFNγ resistance development are frequent in melanoma. Subclones harbouring inactivating mutations emerge under various immunotherapies but are also detectable in pre-treatment biopsies. Our data demonstrate that JAK1/2 deficiency protects melanoma from anti-tumour IFNγ activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFNγ resistance should be considered in therapeutic decision-making.
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spelling pubmed-54600202017-06-12 Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions Sucker, Antje Zhao, Fang Pieper, Natalia Heeke, Christina Maltaner, Raffaela Stadtler, Nadine Real, Birgit Bielefeld, Nicola Howe, Sebastian Weide, Benjamin Gutzmer, Ralf Utikal, Jochen Loquai, Carmen Gogas, Helen Klein-Hitpass, Ludger Zeschnigk, Michael Westendorf, Astrid M. Trilling, Mirko Horn, Susanne Schilling, Bastian Schadendorf, Dirk Griewank, Klaus G. Paschen, Annette Nat Commun Article Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNγ secretion by CD8(+) T cells is critical for therapy efficacy having anti-proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFNγ resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFNγ activity. JAK1/2 mutants further evolve into T-cell-resistant HLA class I-negative lesions with genes involved in antigen presentation silenced and no longer inducible by IFNγ. Allelic JAK1/2 losses predisposing to IFNγ resistance development are frequent in melanoma. Subclones harbouring inactivating mutations emerge under various immunotherapies but are also detectable in pre-treatment biopsies. Our data demonstrate that JAK1/2 deficiency protects melanoma from anti-tumour IFNγ activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFNγ resistance should be considered in therapeutic decision-making. Nature Publishing Group 2017-05-31 /pmc/articles/PMC5460020/ /pubmed/28561041 http://dx.doi.org/10.1038/ncomms15440 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Sucker, Antje
Zhao, Fang
Pieper, Natalia
Heeke, Christina
Maltaner, Raffaela
Stadtler, Nadine
Real, Birgit
Bielefeld, Nicola
Howe, Sebastian
Weide, Benjamin
Gutzmer, Ralf
Utikal, Jochen
Loquai, Carmen
Gogas, Helen
Klein-Hitpass, Ludger
Zeschnigk, Michael
Westendorf, Astrid M.
Trilling, Mirko
Horn, Susanne
Schilling, Bastian
Schadendorf, Dirk
Griewank, Klaus G.
Paschen, Annette
Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions
title Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions
title_full Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions
title_fullStr Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions
title_full_unstemmed Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions
title_short Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions
title_sort acquired ifnγ resistance impairs anti-tumor immunity and gives rise to t-cell-resistant melanoma lesions
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460020/
https://www.ncbi.nlm.nih.gov/pubmed/28561041
http://dx.doi.org/10.1038/ncomms15440
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