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Clonal deletion of thymocytes as a tumor escape mechanism
Author(s) -
Lauritzsen Grete F.,
Hofgaard Peter O.,
Schenck Karl,
Bogen Bjarne
Publication year - 1998
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19981005)78:2<216::aid-ijc16>3.0.co;2-8
Subject(s) - plasmacytoma , biology , idiotype , microbiology and biotechnology , clonal deletion , t cell , t cell receptor , antigen , genetically modified mouse , transgene , cancer research , immunology , antibody , multiple myeloma , monoclonal antibody , immune system , genetics , gene
Clonal deletion of thymocytes is a major event in T‐cell tolerance and might represent a tumor escape mechanism. Previously, we have shown that class II‐restricted, Id‐specific, CD4 + T cells in T‐cell receptor (TCR)‐transgenic mice confer resistance against the MOPC315 plasmacytoma. In this report, we have investigated whether monoclonal immunoglobulin (Ig) produced by a plasmacytoma can induce deletion of thymocytes specific for the variable parts of Ig, i.e., the idiotype (Id). Large numbers of MOPC315 tumor cells were injected s.c. in the TCR‐transgenic mice to overwhelm the CD4 + T‐cell‐mediated protection. When the MOPC315 plasmacytomas reached a weight of approximately 0.5 g (serum myeloma protein M315 about 50 μg/ml), immature CD4 + 8 + and mature CD4 + transgenic thymocytes became progressively deleted. Apoptotic thymocytes were already detectable when tumors were 2 mm in diameter (serum M315: 5 μg/ml, or 0.03 μM). The negative selection was Id‐specific, because an Id‐negative plasmacytoma failed to induce deletion. Injection of purified MOPC315‐myeloma protein (M315) i.p. caused a profound reduction of Id‐specific thymocytes. Enriched thymic dendritic cells (DC) from tumor‐bearing animals were found to be primed with λ2 315 and induced apoptosis of thymocytes in vitro . Our results indicate that circulating myeloma protein is processed and presented by thymic antigen‐presenting cells (APC), and induces deletion of Id‐specific thymocytes. Deletion of tumor‐specific thymocytes may represent a tumor escape mechanism in patients with cancers that secrete or shed tumor antigens. The possibility that vaccination with tumor Ig or genes encoding for it may induce tolerance instead of protection should be taken into consideration. Int. J. Cancer 78:216–222, 1998.© 1998 Wiley‐Liss, Inc.