Tumor antigens recognized by T cells

The study of animal models has clearly demonstrated that the immune system has the capacity to reject tumor cells and that T lymphocytes are instrumental in this rejection. In particular, the essential role of cytotoxic T lymphocytes (CTLs) was highlighted by adoptive transfer studies and by the analysis of tumor variants escaping rejection, which were found to have lost CTL epitopes. A number of mouse tumors were found to express one or several antigens recognized by CTLs derived from lymphocytes of mice having rejected these tumors. In humans, antitumor CTLs were obtained in vitro from the lymphocytes of cancer patients, and a number of antimela-noma CTL clones have been analyzed in detail. The study of melanoma variants that were resistant to some but not all of these CTL clones revealed that melanoma cells express several distinct antigens. The molecular definition of these antigens has afforded crucial insights into both the specificity of these tumor antigens and the mechanism of their expression by tumor cells.

The experimental approach that allowed the identification of most tumor antigens is a genetic approach aimed at cloning the gene that encodes the antigen. This is done by transfecting recombinant libraries into cells that are subsequently screened with the CTL for their expression of the antigen. As observed for viral CTL epitopes, most tumor antigens identified to date do indeed correspond to peptides derived from intracellular proteins and presented at the cell surface by major histocompatibility complex (MHC) class I molecules. Based on the pattern of expression of the parent protein, the antigens can be classified into four major groups: tumor-specific shared antigens, differentiation antigens, antigens resulting from mutations and viral antigens.

Tumor-specific shared antigens

These antigens are encoded by genes that are completely silent in most normal tissues but arc activated in a number of tumors of various histological types. Prototype antigens of this group arc those encoded by gene PIA in the mouse and by genes MAGE in humans. Additional human genes with a similar expression profile have been identified subsequently and are listed in Table 1. Antigenic peptides derived from the proteins encoded by these genes were defined and found to be presented to CTLs by specific MHC class I molecules (Table 1). With the exception of RAGE, the only normal cells where

Table 1 Tumor-specific antigens shared by different tumors

Gene

Normal expression

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