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Cancer Res. 2016 Aug 1;76(15):4347-58. doi: 10.1158/0008-5472.CAN-16-0008. Epub 2016 Jun 3.

Melanoma Lesions Independently Acquire T-cell Resistance during Metastatic Latency.

Author information

1
Department of Dermatology, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany.
2
Internal Medicine III, University Cancer Center (UCT) and Research Center for Immunotherapy (FZI), University Medical Center (UMC), Johannes Gutenberg University and German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Mainz, Germany.
3
Institute of Molecular Genetics, Genetic Engineering Research and Consulting, Johannes Gutenberg University, Mainz, Germany.
4
Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
5
Department of Immunology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
6
Translational Skin Cancer Research, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany.
7
Department of Dermatology, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany. annette.paschen@uk-essen.de.

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 class I loss in both metastases originated from a shared chromosome 15q alteration and independently acquired focal B2M gene deletions. A third HLA class I haplotype-deficient lesion developed in year 3 of stage IV disease that acquired resistance toward dominant CD8(+) T-cell clonotypes targeting stage III tumor cells. At an early stage, melanoma cells showed a dedifferentiated c-Jun(high)/MITF(low) phenotype, possibly associated with immunosuppression, which contrasted with a c-Jun(low)/MITF(high) phenotype of T cell-edited tumor cells derived from late metastases. In summary, our work shows how tumor recurrences after long-term latency evolve toward T-cell resistance by independent genetic events, as a means for immune escape and immunotherapeutic resistance. Cancer Res; 76(15); 4347-58.

PMID:
27261508
DOI:
10.1158/0008-5472.CAN-16-0008
[Indexed for MEDLINE]
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