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Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions
- Source :
- Nature Communications, Nature Communications, Vol 8, Iss 1, Pp 1-15 (2017)
- Publication Year :
- 2017
- Publisher :
- Springer Science and Business Media LLC, 2017.
-
Abstract
- 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.<br />IFNγ secretion by CD8+ T cells is critical for immunotherapy efficacy. In this study, the authors show that melanoma patients can become resistant to immunotherapy by acquiring chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2.
- Subjects :
- Patient-Specific Modeling
0301 basic medicine
Skin Neoplasms
Biopsy
T-Lymphocytes
DNA Mutational Analysis
Datasets as Topic
General Physics and Astronomy
Antineoplastic Agents, Immunological
Mutation Rate
Precision Medicine
Melanoma
Skin
Antigen Presentation
Multidisciplinary
biology
food and beverages
3. Good health
Treatment Outcome
medicine.anatomical_structure
Immunotherapy
Antibody
Signal Transduction
Science
T cell
Antigen presentation
Human leukocyte antigen
Article
General Biochemistry, Genetics and Molecular Biology
Interferon-gamma
03 medical and health sciences
Antigen
Antigens, Neoplasm
Cell Line, Tumor
medicine
Humans
Whole Genome Sequencing
Histocompatibility Antigens Class I
Janus Kinase 1
General Chemistry
Janus Kinase 2
medicine.disease
030104 developmental biology
Immunoediting
Drug Resistance, Neoplasm
Mutation
Immunology
biology.protein
Tumor Escape
CD8
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....fe4cfe1b9a8a6acb58788bf15c62d90f