0000000000158314
AUTHOR
Susanne Horn
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 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 …
Genetic evolution of T-cell resistance in the course of melanoma progression
Abstract Purpose: CD8+ T lymphocytes can kill autologous melanoma cells, but their activity is impaired when poorly immunogenic tumor phenotypes evolve in the course of disease progression. Here, we analyzed three consecutive melanoma lesions obtained within one year of developing stage IV disease for their recognition by autologous T cells. Experimental Design: One skin (Ma-Mel-48a) and two lymph node (Ma-Mel-48b, Ma-Mel-48c) metastases were analyzed for T-cell infiltration. Melanoma cell lines established from the respective lesions were characterized, determining the T-cell–stimulatory capacity, expression of surface molecules involved in T-cell activation, and specific genetic alteratio…
Melanoma Lesions Independently Acquire T-cell Resistance during Metastatic Latency
Abstract Melanoma often recurs after a latency period of several years, presenting a T cell–edited phenotype that reflects a role for CD8+ T cells in maintaining metastatic latency. Here, we report an investigation of a patient with multiple recurrent lesions, where poorly immunogenic melanoma phenotypes were found to evolve in the presence of autologous tumor antigen–specific CD8+ T cells. Melanoma cells from two of three late recurrent metastases, developing within a 6-year latency period, lacked HLA class I expression. CD8+ T cell–resistant, HLA class I–negative tumor cells became clinically apparent 1.5 and 6 years into stage IV disease. Genome profiling by SNP arrays revealed that HLA …
Large- and Fine-Scale Geochemical Variations Along the Andean Arc of Northern Chile (17.5°– 22°S)
Geochemical data from 37 volcanic centres from the active volcanic front in the Central Andes between 17.5° and 22°S of northern Chile provide constraints on crustal contributions to arc magma genesis in that region. Crustal thickness, distance from the trench, height above the seismically active subduction zone, and sediment supply to the trench are all constant along this segment of the arc. The only significant variable along the current arc segment is in mean crustal age (Palaeozoic in the south to Proterozoic in the north). In addition, the crustal thickness has varied through time from around 40 km in the Lower Miocene to about 70 km today. Variations along the N-S chain of the volcan…