Melanoma Lesions Independently Acquire T-cell Resistance during Metastatic Latency.
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. ©2016 AACR.
Department of Dermatology, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany.
Fang
F
Zhao
Department of Dermatology, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany.
Antje
A
Sucker
Department of Dermatology, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany.
Susanne
S
Horn
Department of Dermatology, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany.
Christina
C
Heeke
Department of Dermatology, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany.
Nicola
N
Bielefeld
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.
Barbara
B
Schrörs
Institute of Molecular Genetics, Genetic Engineering Research and Consulting, Johannes Gutenberg University, Mainz, Germany.
Anne
A
Bicker
Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Monika
M
Lindemann
Department of Dermatology, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany.
Alexander
A
Roesch
Department of Immunology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
Gustav
G
Gaudernack
Translational Skin Cancer Research, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany.
Mathias
M
Stiller
Translational Skin Cancer Research, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany.
Jürgen C
JC
Becker
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.
Volker
V
Lennerz
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.
Thomas
T
Wölfel
Department of Dermatology, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany.
Dirk
D
Schadendorf
Department of Dermatology, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany.
Klaus
K
Griewank
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.
Annette
A
Paschen
D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000276:immunology*
D000951:Antigens, Neoplasm; D009363:Neoplasm Proteins