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T-cell immune function in tumor, skin, and peripheral blood of advanced stage melanoma patients: implications for immunotherapy

Authors :
John B. A. G. Haanen
Chantal M.A.M. van der Horst
Jan W. Drijfhout
Jan D. Bos
Kees L. M. C. Franken
Cornelis J. M. Melief
Omgo E. Nieweg
Esther P. M. Tjin
Florry A. Vyth-Dreese
H. Mallo
Rosalie M. Luiten
Gabrielle Krebbers
Bin B. R. Kroon
Debby Konijnenberg
Amsterdam institute for Infection and Immunity
Cancer Center Amsterdam
Dermatology
Other departments
Amsterdam Cardiovascular Sciences
Other Research
Plastic, Reconstructive and Hand Surgery
Surgery
Source :
Clinical cancer research, 17(17), 5736-5747. American Association for Cancer Research Inc.
Publication Year :
2011

Abstract

Purpose: To predict the potential antitumor effect of antigen-specific T cells in melanoma patients, we investigated T-cell effector function in relation to tumor-escape mechanisms. Experimental Design: CD8+ T cells isolated from tumor, adjacent normal skin, and peripheral blood of 17 HLA-A2+ patients with advanced-stage melanoma were analyzed for their antigen specificity and effector function against melanocyte differentiation antigens MART-1, gp100, and tyrosinase by using HLA-A2/peptide tetramers and functional assays. In addition, the presence of tumor-escape mechanisms PD-L1/PD-1 pathway, FoxP3 and loss of HLA or melanocyte differentiation antigens, both required for tumor cell recognition and killing, were studied. Results: Higher percentages of melanocyte antigen-specific CD8+ T cells were found in the melanoma tissues as compared with adjacent normal skin and peripheral blood. Functional analysis revealed 2 important findings: (i) in 5 of 17 patients, we found cytokine production after specific peptide stimulation by tumor-infiltrating lymphocytes (TIL), not by autologous peripheral blood lymphocytes (PBL); (ii) CD8+ T cells from 7 of 17 patients did not produce cytokines after specific stimulation, which corresponded with significant loss of tumor HLA-A2 expression. The presence of other tumor-escape mechanisms did not correlate to T-cell function. Conclusions: Our data show that functional T-cell responses could be missed when only PBL and not TIL are evaluated, emphasizing the importance of TIL analysis for immunomonitoring. Furthermore, loss of tumor HLA-A2 may explain the lack of T-cell functionality. These findings have important implications for selecting melanoma patients who may benefit from immunotherapy. Clin Cancer Res; 17(17); 5736–47. ©2011 AACR.

Details

Language :
English
ISSN :
10780432
Database :
OpenAIRE
Journal :
Clinical cancer research, 17(17), 5736-5747. American Association for Cancer Research Inc.
Accession number :
edsair.doi.dedup.....b6e29ab6c0870350c0cebd34048bdd31