Genetic Evolution of T-cell Resistance in the Course of Melanoma Progression
Open Access
- 7 October 2014
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 20 (24), 6593-6604
- https://doi.org/10.1158/1078-0432.ccr-14-0567
Abstract
Purpose: 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.Experimental Design: 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.Conclusion: 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. Clin Cancer Res; 20(24); 6593–604. ©2014 AACR.Other Versions
This publication has 46 references indexed in Scilit:
- Tumor Exome Analysis Reveals Neoantigen-Specific T-Cell Reactivity in an Ipilimumab-Responsive MelanomaJournal of Clinical Oncology, 2013
- Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cellsNature Medicine, 2013
- 12-Chemokine Gene Signature Identifies Lymph Node-like Structures in Melanoma: Potential for Patient Selection for Immunotherapy?Scientific Reports, 2012
- Unexpected role for MHC II–peptide complexes in shaping CD8 T-cell expansion and differentiation in vivoProceedings of the National Academy of Sciences of the United States of America, 2012
- Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced CancerThe New England Journal of Medicine, 2012
- Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in CancerThe New England Journal of Medicine, 2012
- Immunotype and Immunohistologic Characteristics of Tumor-Infiltrating Immune Cells Are Associated with Clinical Outcome in Metastatic MelanomaCancer Research, 2012
- Improved Survival with Ipilimumab in Patients with Metastatic MelanomaThe New England Journal of Medicine, 2010
- Chemokine Expression in Melanoma Metastases Associated with CD8+ T-Cell RecruitmentCancer Research, 2009
- ICAM-1 Has a Critical Role in the Regulation of Metastatic Melanoma Tumor Susceptibility to CTL Lysis by Interfering with PI3K/AKT PathwayCancer Research, 2008