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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)
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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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift Journal of Clinical Investigation
Quellenangaben Band: 120, Heft: 11, Seiten: 3869-3877 Artikelnummer: , Supplement: ,
Verlag American Society of Clinical Investigation
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Immunology (IMI)
CCG Immune Monitoring (Platform) (IMI-KIM)