CLONAL DELETION OF THYMOCYTES AS A TUMOR ESCAPE MECHANISM

Clonal deletion of thymocytes is a major event in T-cell tolerance and might represent a tumor escape mechanism. Previously, we have shown t hat class Ii-restricted, Id-specific, CD4(+) T cells in T-cell recepto r (TCR)-transgenic mice confer resistance against the MOPC315 plasmacy toma. In this report, we have investigated whether monoclonal immunogl obulin (Ig) produced by a plasmacytoma can induce deletion of thymocyt es specific for the variable parts of Ig, i.e., the idiotype (Id), Lar ge numbers of MOPC315 tumor cells were injected s.c. in the TCR-transg enic 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 mu g/ml), immature CD4(+)8(+) and mature CD4+ transgenic thymocytes became progressively deleted. Apoptotic th ymocytes were already detectable when tumors were 2 mm in diameter (se rum M315: 5 mu g/ml, or 0.03 mu M), The negative selection was Id-spec ific, because an Id-negative plasmacytoma failed to induce deletion. I njection of purified MOPC315-myeloma protein (M315) i.p. caused a prof ound reduction of Id specific thymocytes, Enriched thymic dendritic ce lls (DC) from tumor-bearing animate were found to be primed with lambd a 2(315) and induced apoptosis of thymocytes in vitro, Our results ind icate that circulating myeloma protein is processed and presented by t hymic antigen-presenting cells (APC), and induces deletion of Id-speci fic thymocytes. Deletion of tumor-specific thymocytes may represent a tumor escape mechanism in patients with cancers that secrete or shed t umor antigens, The possibility that vaccination with tumor Ig or genes encoding for it may induce tolerance instead of protection should be taken into consideration. (C) 1998 Wiley-Liss, Inc.