Monitoring of antigen-specific cytolytic T lymphocytes in cancer patients receiving immunotherapy.

Abstract

Recent progress in molecular and immunologic approaches to discovery of tumor-associated antigens (TAA) in humans has resulted in the characterization of a number of new epitopes (3, 23). In most cases, the success of these efforts depended on the availability of tumor-specific T-cell lines or clones, which were used as probes for isolation and biochemical characterization of TAA (10, 55). Two types of methodologies have largely been used for antigen discovery: (i) biochemical fractionation of naturally processed and presented peptides derived from major histocompatibility complex (MHC) class I molecules expressed by tumor cells (16) and (ii) expression cloning of cells transfected with cDNA libraries derived from tumor cells (54). More recent introduction of the SEREX (serological analysis of tumor antigens by recombinant cDNA expression cloning) technology (47) and of computer-based modeling of peptides that best fit the relevant MHC class I molecules expressed on tumor cells (15) further expands the list of technologies available for antigen discovery and for identification of TAA which might be therapeutically useful. SEREX is based on identification of recombinant tumor antigens by immunoglobulin G (IgG) antibodies present in the patient’s serum. To qualify for immunotherapy, e.g., as components of antitumor vaccines, TAA or their newly identified epitopes have to be immunogenic, that is, able to induce and sustain an immune response specifically targeted not only to the immunizing epitope but to the tumor itself. With the exception of the products of mutated genes, few if any TAA epitopes meet the criteria for therapeutic utility, largely because they are self-antigens rather than neo-antigens. As such, they are weakly immunogenic, and tolerance for self-epitopes in tumor-bearing hosts prevents generation of strong antitumor immune responses targeting these TAA. Most of the melanoma-derived peptides are normal differentiation antigens, which are overexpressed in tumor cells (3, 9, 23). The TAA encoded by mutated genes are the exception, of course, because they are truly new antigens, but their therapeutic usefulness is limited to individually tailored treatments that are not applicable to broad-scale immunizations. Nearly all of the known TAA epitopes are ligands for T-cell receptors (TcRs) which are clonally expressed on T lymphocytes: on CD8 1 T cells expressing TcRs for nanopeptides associated with MHC class I molecules or on CD4 1 T cells