Danger Versus Tolerance: Paradigms for Future Studies of Tumor-Specific Cytotoxic T Lymphocytes

Extract

The field of tumor immunology has made important scientific advances during the past 10 years. One major advance has been the identification of major histocompatability complex (MHC) class I-restricted human tumor antigens that act as targets for cytotoxic T lymphocytes (CTLs), at least in vitro ( 1 ). Much of the pioneering work has been performed in melanoma, where a number of tumor antigen genes have been isolated and shown to fall into two main groups based on their pattern of gene expression. One group includes the MAGE/GAGE/BAGE gene families, which are expressed by a variety of different tumors but not by normal cells in adults (with the exception of testes) ( 1 ). The normal functions of the proteins encoded by these genes remain obscure. The second group includes genes encoding tyrosinase, MART-1, TRP-1, and gp100, which are normally expressed in pigmented cells and whose expression is maintained in tumors derived from melanocytes ( 2 ). These are lineage-specific differentiation antigens that are not mutated or overexpressed in melanoma cells. That, in some cases, these antigens were identified by use of CD8+ tumor-infiltrating lymphocytes (TILs) isolated from patients' tumors was an early indication of an important paradigm that has evolved as a result of these data. The new concept is that tumor antigens are often normal self-proteins to which tolerance can be broken. This concept, in turn, leads to the hypothesis that, under normal circumstances, tolerance exists only for dominant epitopes, while the T-cell repertoire directed against cryptic (or subdominant) self-antigens remains largely intact. Other examples have recently been described. For instance, overexpression of normal cellular proteins in tumor cells, which results from gene amplification or transcriptional enhancement [i.e., HER2/neu ( 3 )] or from stabilization of protein half-life by point mutation [p53 ( 4 )], appears to be important both in the genetic evolution of the cancer cell and in increasing the presentation of peptides derived from these tumor antigens. In the case of p53, an important recent finding is that T-cell immunity can be efficiently directed at nonmutated epitopes within the p53 protein ( 4 ), which greatly increases the likelihood that multiple MHC class I molecules will be able to bind and present antigenic peptides derived from p53.