title: Genetic evolution of T-cell resistance in the course of melanoma progression.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 alterations affecting the tumor-T-cell interaction.
  
  
  RESULTS
  Metastases Ma-Mel-48a and Ma-Mel-48b, in contrast with Ma-Mel-48c, were infiltrated by T cells. The T-cell-stimulatory capacity was found to be strong for Ma-Mel-48a, lower for Ma-Mel-48b, and completely abrogated for Ma-Mel-48c cells. The latter proved to be HLA class I-negative due to an inactivating mutation in one allele of the beta-2-microglobulin (B2M) gene and concomitant loss of the other allele by a deletion on chromosome 15q. The same deletion was already present in Ma-Mel-48a and Ma-Mel-48b cells, pointing to an early acquired genetic event predisposing to development of β2m deficiency. Notably, the same chronology of genetic alterations was also observed in a second β2m-deficient melanoma model.
  
  
  CONCLUSIONS
  Our study reveals a progressive loss in melanoma immunogenicity during the course of metastatic disease. The genetic evolvement of T-cell resistance suggests screening tumors for genetic alterations affecting immunogenicity could be clinically relevant in terms of predicting patient responses to T-cell-based immunotherapy.
authors.affiliation: Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Sucker
authors.affiliation: Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Germany.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Real
authors.affiliation: Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Heeke
authors.affiliation: Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Bielefeld
authors.affiliation: Institute of Transplant Immunology, IFB-Tx, Hannover Medical School, Hannover, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Maβen
authors.affiliation: Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Horn
authors.affiliation: Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Moll
authors.affiliation: Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Germany.
authors.forename: Raffaela
authors.initials: R
authors.lastname: Maltaner
authors.affiliation: German Cancer Consortium (DKTK), Germany. Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Horn
authors.affiliation: Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Schilling
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sabbatino
authors.affiliation: Medical Oncology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Lennerz
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.affiliation: Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Institute of Transplant Immunology, IFB-Tx, Hannover Medical School, Hannover, Germany.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Falk
authors.affiliation: Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Griewank
authors.affiliation: Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Germany. annette.paschen@uk-essen.de.
authors.forename: Annette
authors.initials: A
authors.lastname: Paschen
mesh_terms: D000483:Alleles; D060887:B7 Antigens / Q000235:genetics / Q000276:immunology; D002077:Butorphanol; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D019143:Evolution, Molecular; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics
chemical_list: D060887:B7 Antigens; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D001613:beta 2-Microglobulin; D002077:Butorphanol