PuSH - Publication Server of Helmholtz Zentrum München

Leisegang, M.* ; Wilde, S. ; Spranger, S. ; Milosevic, S. ; Frankenberger, B. ; Uckert, W.* ; Schendel, D.J.

MHC-restricted fratricide of human lymphocytes expressing survivin-specific transgenic T cell receptors.

J. Clin. Invest. 120, 3869-3877 (2010)
Publ. Version/Full Text Volltext DOI PMC
Free by publisher
Open Access Green as soon as Postprint is submitted to ZB.
The apoptosis inhibitor protein survivin is overexpressed in many tumors, making it a candidate target molecule for various forms of immunotherapy. To explore survivin as a target antigen for adoptive T cell therapy using lymphocytes expressing survivin-specific transgenic T cell receptors (Tg-TCRs), we isolated HLA-A2-allorestricted survivin-specific T cells with high functional avidity. Lymphocytes expressing Tg-TCRs were derived from these T cells and specifically recognized HLA-A2+ survivin+ tumor cells. Surprisingly, HLA-A2+ but not HLA-A2- lymphocytes expressing Tg-TCRs underwent extensive apoptosis over time. This demise was caused by HLA-A2-restricted fratricide that occurred due to survivin expression in lymphocytes, which created ligands for Tg-TCR recognition. Therefore, survivin-specific TCR gene therapy would be limited to application in HLA-A2-mismatched stem cell transplantation. We also noted that lymphocytes that expressed survivin-specific Tg-TCRs killed T cell clones of various specificities derived from HLA-A2+ but not HLA-A2- donors. These results raise a general question regarding the development of cancer vaccines that target proteins that are also expressed in activated lymphocytes, since induction of high-avidity T cells that expand in lymph nodes following vaccination or later accumulate at tumor sites might limit themselves by self-MHC-restricted fratricide while at the same time inadvertently eliminating neighboring T cells of other specificities.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords INHIBITOR PROTEIN SURVIVIN; CANCER-IMMUNOTHERAPY; ANTITUMOR-ACTIVITY; MELANOMA-CELLS; GENE-THERAPY; HIGH-AVIDITY; EX-VIVO; ANTIGEN; APOPTOSIS; IDENTIFICATION
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Journal Journal of Clinical Investigation
Quellenangaben Volume: 120, Issue: 11, Pages: 3869-3877 Article Number: , Supplement: ,
Publisher American Society of Clinical Investigation
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Immunology (IMI)
CCG Immune Monitoring (Platform) (IMI-KIM)