ABSTRACT
The evidence for the existence of tumor-specific antigens leading to tumor rejection was obtained almost 50 years ago (Prehn and Main, 1957). At that time it was shown that chemically induced, transplanted mouse tumors can be rejected if the recipient mice have been previously rendered “immune” to the same tumor by a single round of tumor growth and surgical excision. Rejection of neoplastic cells was tumor-specific, since no protection against subsequent tumor growth could be achieved by transplanting normal tissues or tumor cells different from those used for challenge. Although the initial experiments performed by Foley, Prehn and the Kleins in the 1950s and 1960s formally established the existence of TSTA, it took more than 35 years of research in molecular biology, immunology, and genetics to understand the molecular nature of tumor antigens. This achievement, obtained for the first time by T.Boon and his group, first in mouse and then in human tumors at the beginning of the 1990s (see Boon et al., 1994), represented the final success of a long chain of discoveries that contributed to the shaping of modern immunology. The discovery of the MHC restriction in 1974 by Zinkernagel and Doherty, the elucidation of the crystal structure of HLA molecules in 1987 by P.Bjorkmann, and the understanding of the genetic basis for the expression and function of TCRs by M.Davis in 1984 are just a few of the seminal findings that opened the way to deciphering the molecular nature of antigens recognized by T cells, including tumor antigens. We now know that tumor antigens recognized by T cells are short peptides bound to MHC class I or II molecules. The MHC-peptide complex is the “antigenic
epitope” recognized by the specific receptor for antigen (TCR) expressed by each T cell. The rules dictating how a T cell will recognize the peptide antigen for which it possesses a specific TCR are universal; therefore, at the structural level T cell recognition of a tumor antigen is no different from recognition of viral antigens on an infected cell (see Figure 3.1). The elucidation of the structure of the TCR has revealed a clonally distributed heterodimer made up of two chains (α and β) bound by a disulphide link. Each of the two TCR chains is transcribed from families of gene segments coding for the variable (V), joining (J) and constant (C) regions. The β chain contains an additional D region. Somatic rearrangement, taking place during T cell differentatiation within the thymus, joins together different VDJ segments that are then linked by splicing to the constant region transcripts. The region of the TCR coded for by the V, J and D regions represents the most important segment for interaction with the ligand (the MHC-peptide complex) and is named CDR3 (complementarity determining region 3, Figure 3.1). The unique sequences in the CDR3 region contribute to defining the ligand specificity of the TCR. By taking advantage of these unique sequences, it is even possible to identify and quantitate in vivo (in lesions) or in vitro (in T cell lines selected for tumor recognition) tumor-specific T cells.
