title: Regression of melanoma metastases after immunotherapy is associated with activation of antigen presentation and interferon-mediated rejection genes.
abstract: We present the results of a comparative gene expression analysis of 15 metastases (10 regressing and 5 progressing) obtained from 2 melanoma patients with mixed response following different forms of immunotherapy. Whole genome transcriptional analysis clearly indicate that regression of melanoma metastases is due to an acute immune rejection mediated by the upregulation of genes involved in antigen presentation and interferon mediated response (STAT-1/IRF-1) in all the regressing metastases from both patients. In contrast, progressing metastases showed low transcription levels of genes involved in these pathways. Histological analysis showed T cells and HLA-DR positive infiltrating cells in the regressing but not in the progressing metastases. Quantitative expression analysis of HLA-A,B and C genes on microdisected tumoral regions indicate higher HLA expression in regressing than in progressing metastases. The molecular signature obtained in melanoma rejection appeared to be similar to that observed in other forms of immune-mediated tissue-specific rejection such as allograft, pathogen clearance, graft versus host or autoimmune disease, supporting the immunological constant of rejection. We favor the idea that the major factor determining the success or failure of immunotherapy is the nature of HLA Class I alterations in tumor cells and not the type of immunotherapy used. If the molecular alteration is reversible by the immunotherapy, the HLA expression will be upregulated and the lesion will be recognized and rejected. In contrast, if the defect is structural the MHC Class I expression will remain unchanged and the lesion will progress.
authors.affiliation: Departamento de Bioquímica, Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Carretero
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Ana I
authors.initials: AI
authors.lastname: Rodriguez
authors.forename: Jennifer
authors.initials: J
authors.lastname: Reinboth
authors.forename: Maria L
authors.initials: ML
authors.lastname: Ascierto
authors.forename: Alyson M
authors.initials: AM
authors.lastname: Engle
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Camacho
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.forename: Federico
authors.initials: F
authors.lastname: Garrido
authors.forename: Teresa
authors.initials: T
authors.lastname: Cabrera
mesh_terms: D017951:Antigen Presentation / Q000235:genetics* / Q000276:immunology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015234:HLA-A Antigens / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D007167:Immunotherapy; D050856:Interferon Regulatory Factor-1 / Q000235:genetics; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000556:secondary / Q000628:therapy*; D009362:Neoplasm Metastasis; D050794:STAT1 Transcription Factor / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D006684:HLA-DR Antigens; D050856:Interferon Regulatory Factor-1; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human