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Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer.

Abstract：

:We identified a tumor-associated cytotoxic T lymphocyte (CTL) epitope derived from the widely expressed human MDM2 oncoprotein and were able to bypass self-tolerance to this tumor antigen in HLA-A*0201 (A2.1) transgenic mice and by generating A2.1-negative, allo-A2.1-restricted human T lymphocytes. A broad range of malignant, as opposed to nontransformed cells, were killed by high-avidity transgenic mouse and allogeneic human CTLs specific for the A2.1-presented MDM2 epitope. Whereas the self-A2.1-restricted human T cell repertoire gave rise only to low-avidity CTLs unable to recognize the natural MDM2 peptide, human A2.1+ T lymphocytes were turned into efficient MDM2-specific CTLs upon expression of wild-type and partially humanized high-affinity T cell antigen receptor (TCR) genes derived from the transgenic mice. These results demonstrate that TCR gene transfer can be used to circumvent self-tolerance of autologous T lymphocytes to universal tumor antigens and thus provide the basis for a TCR gene transfer-based broad-spectrum immunotherapy of malignant disease.

journal_name

Nat Immunol

journal_title

Nature immunology

authors

Stanislawski T,Voss RH,Lotz C,Sadovnikova E,Willemsen RA,Kuball J,Ruppert T,Bolhuis RL,Melief CJ,Huber C,Stauss HJ,Theobald M

doi

10.1038/ni1001-962

keywords:

subject

Has Abstract

pub_date

2001-10-01 00:00:00

pages

962-70

issue

10

eissn

1529-2908

issn

1529-2916

pii

ni1001-962

journal_volume

2

pub_type

杂志文章

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