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

Content Provider	Semantic Scholar
Author	Whiteside, Theresa L.
Copyright Year	2000
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 T cells expressing TcRs for nanopeptides associated with MHC class I molecules or on CD4 T cells responding to larger peptides presented by MHC class II molecules (32). The presentation of TAA-derived peptides to T cells could be accomplished by tumor cells themselves, provided they express MHC molecules (29). However, since most human tumors express abnormally low levels of class I molecules (17) and may have no or low expression of class II antigens (32), in vivo presentation of TAA-derived peptides to immune cells is likely to occur by the process mediated by dendritic cells (DC) and referred to as “cross-presentation.” The importance of DC in immune responses to TAA has been emphasized in view of emerging evidence for frequent, if not universal, defective antigen processing in tumor cells (26, 50). This then means that DC can internalize and process TAA for presentation to T cells bearing the appropriate TcRs, bypassing the need for tumor cells to act as antigen-presenting cells (APC). Still, even if DC assume the role of TAA presentation in vivo and cytolytic T lymphocytes (CTL) are generated as a result of effective cross-presentation, these CTL have to be able to access the tumor site and recognize the relevant peptides expressed on the surface of tumor cells in the context of MHC molecules in order to initiate tumor cell lysis. Therefore, expression on the tumor cell surface of the MHC-peptide complexes is a prerequisite for immunologic recognition and immune cell-mediated tumor cell destruction. TAA-specific T-cell responses following immunotherapy, and particularly after the administration of natural or synthetic anticancer vaccines, have been studied in patients with cancer (28, 34, 46). Early clinical trials evaluating such vaccines showed tumor regression even in patients with advanced disease (28, 34, 46). Quantitation of antigen-reactive T cells prior to, during, and after therapy is crucial for future development of antitumor vaccines. To detect the frequency of peptide-, protein-, or tumor-specific T cells in the peripheral circulation of patients treated with anticancer vaccines, several methods have been developed. The objective aimed for is a measure of effectiveness of therapy, as judged by the increased number of circulating specific T cells responsive to vaccinating antigens and, optimally, to autologous tumor cells as well. The assays available for measuring of TAA-reactive T cells include (i) cytotoxicity assays, which provide the assessment of the ability of T-cell populations to lyse tumor cells, (ii) cytokine expression or production assays, in which TAA-specific responses of T cells are evaluated based on antibody-mediated detection of intracellular cytokines or cytokines released by T cells following stimulation with the relevant antigen, (iii) direct quantitation in peripheral blood mononuclear cells (PBMC) of T cells able to recognize and bind to a labeled peptide-MHC complex, and (iv) enumeration of T cells expressing a specific type of TcR, using PCR-based amplification. The purpose of this review is to briefly consider advantages as well as disadvantages of these methodologies for monitoring of TAA-specific responses in patients with cancer treated with antitumor vaccines and other immunotherapies. * Mailing address: University of Pittsburgh Cancer Institute, W 1041 Biomedical Science Tower, 211 Lothrop St., Pittsburgh, PA 152132582. Phone: (412) 624-0096. Fax: (412) 624-0264. E-mail: whitesidetl @msx.upmc.edu
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Alternate Webpage(s)	http://cvi.asm.org/content/7/3/327.full.pdf
Alternate Webpage(s)	http://www.cytoluminator.com/cancer-photodynamic-therapy/monitoring%20of%20cytolytic%20T%20Lymphocytes.pdf
PubMed reference number	10799441v1
Volume Number	7
Issue Number	3
Journal	Clinical and diagnostic laboratory immunology
Language	English
Access Restriction	Open
Subject Keyword	Antigen Presentation Antigen Processing Autologous Tumor Cell Biological Response Modifier Therapy CD4 Positive T Lymphocytes Cross-Presentation Cytotoxic T-Lymphocytes DNA, Complementary Dendritic Cells Differentiation Antigens Email Epitopes Estimated HLA-D Antigens Helper-Inducer T-Lymphocyte Immunization Immunoglobulin G Immunotherapy Large Leukemia, B-Cell Ligands Lysis Major Histocompatibility Complex Neoplasms Patients Peripheral blood mononuclear cell (cell) Quantitation Receptors, Cell Surface Recombinants SARS coronavirus T-cell receptor complex location Therapeutic procedure Tracer Tumor Antigens cellular targeting cytokine pathologic cytolysis varicella-zoster immune globulin
Content Type	Text
Resource Type	Article