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

5 years ago

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

Susanne Horn, Ludger Klein-Hitpass, Bastian Schilling, Helen Gogas, Astrid M. Westendorf, Mirko Trilling, Fang Zhao, Birgit Real, Carmen Loquai, Michael Zeschnigk, Sebastian Howe, Natalia Pieper, Nicola Bielefeld, Klaus G. Griewank, Christina Heeke, Nadine Stadtler, Dirk Schadendorf, Benjamin Weide, Annette Paschen, Raffaela Maltaner, Jochen Utikal, Antje Sucker, Ralf Gutzmer

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.

Publisher URL: http://www.nature.com/articles/ncomms15440

DOI: 10.1038/ncomms15440