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

ABSTRACT: Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFN? 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 IFN? resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFN? signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFN? 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 IFN?. Allelic JAK1/2 losses predisposing to IFN? 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 IFN? activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFN? resistance should be considered in therapeutic decision-making.

SUBMITTER: Sucker A

PROVIDER: S-EPMC5460020 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Sucker Antje A Zhao Fang F Pieper Natalia N Heeke Christina C Maltaner Raffaela R Stadtler Nadine N Real Birgit B Bielefeld Nicola N Howe Sebastian S Weide Benjamin B Gutzmer Ralf R Utikal Jochen J Loquai Carmen C Gogas Helen H Klein-Hitpass Ludger L Zeschnigk Michael M Westendorf Astrid M AM Trilling Mirko M Horn Susanne S Schilling Bastian B Schadendorf Dirk D Griewank Klaus G KG Paschen Annette A

Nature communications 20170531

Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNγ secretion by CD8<sup>+</sup> 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 activ ...[more]

PMID: 28561041

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Project description:Severe liver diseases are characterized by expansion of liver progenitor cells (LPC), which correlates with disease severity. However, the origin and role of LPC in liver physiology and in hepatic injury remains a contentious topic. We found that ductular reaction cells in human cirrhotic livers express hepatocyte nuclear factor 1 homeobox B (HNF1?). However, HNF1? expression was not present in newly generated epithelial cell adhesion molecule (EpCAM)-positive hepatocytes. In order to investigate the role of HNF1?-expressing cells we used a tamoxifen-inducible Hnf1?CreER/R26R(Yfp/LacZ) mouse to lineage-trace Hnf1?(+) biliary duct cells and to assess their contribution to LPC expansion and hepatocyte generation. Lineage tracing demonstrated no contribution of HNF1?(+) cells to hepatocytes during liver homeostasis in healthy mice or after loss of liver mass. After acute acetaminophen or carbon tetrachloride injury no contribution of HNF1?(+) cells to hepatocyte was detected. We next assessed the contribution of Hnf1?(+) -derived cells following two liver injury models with LPC expansion, a diethoxycarbonyl-1,4-dihydro-collidin (DDC)-diet and a choline-deficient ethionine-supplemented (CDE)-diet. The contribution of Hnf1?(+) cells to liver regeneration was dependent on the liver injury model. While no contribution was observed after DDC-diet treatment, mice fed with a CDE-diet showed a small population of hepatocytes derived from Hnf1?(+) cells that were expanded to 1.86% of total hepatocytes after injury recovery. Genome-wide expression profile of Hnf1?(+) -derived cells from the DDC and CDE models indicated that no contribution of LPC to hepatocytes was associated with LPC expression of genes related to telomere maintenance, inflammation, and chemokine signaling pathways.HNF1?(+) biliary duct cells are the origin of LPC. HNF1?(+) cells do not contribute to hepatocyte turnover in the healthy liver, but after certain liver injury, they can differentiate to hepatocytes contributing to liver regeneration.

Dataset Information

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

Publications

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

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