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. IFNg 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 IFNg resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNg signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFNg 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 IFNg. Allelic JAK1/2 losses predisposing to IFNg 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 IFNg activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFNg resistance should be considered in therapeutic decision-making.