Regression of melanoma metastases after immunotherapy is associated with activation of antigen presentation and interferon-mediated rejection genes
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AuthorCarretero Coca, Rafael; Wang, Ena; Rodríguez, Ana I.; Reinboth, Jennifer; Ascierto, María L.; Engle, Alyson M.; Liu, Hui; Camacho, Francisco M.; Marincola, Francesco M.; Garrido Torres-Puchol, Federico; Cabrera Castillo, María Teresa
International Union against Cancer (UICC)
Carretero, R.; et al. Regression of melanoma metastases after immunotherapy is associated with activation of antigen presentation and interferon-mediated rejection genes. International Journal of Cancer, 131(2): 387-395 (2012). [The definitive version is available at www3.interscience.wiley.com]. [http://hdl.handle.net/10481/29170]
SponsorshipFondo de Investigaciones Sanitarias (FIS). Grant Numbers: CP03/0111, PI 08/1265. Proyecto de investigacion MEC I + D. Grant Numbers: SAF 2007-63262, SAF 2010-20273. Red Genomica del Cancer. Grant Number: RETIC RD 06/020. Plan Andaluz de Investigacion. Grant Numbers: CTS 143, CTS-695. Proyectos de Excelencia. Grant Numbers: CTS-03952, CVI-04740. Integrated European Cancer Immunotherapy. Grant Numbers: OJ2004/C158, 518234.
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.