Recognition of carcinoembryonic antigen peptide and heteroclitic peptide by peripheral blood T lymphocytes.
The carcinoembryonic antigen (CEA)-derived peptide CAP1 and heteroclitic peptide CAP1-6D are stimulators of HLA-A*A0201 restricted CEA-specific T cells in vivo and in vitro. The goal of this study was to evaluate differences in T cell responses to peptide and modified peptide antigens from CEA. The heterogeneity of responses among individuals is potentially important for the design of future CEA-directed immunotherapy trials. Peripheral blood mononuclear cells from blood donors were stimulated with peptide, IL-2, and IL-7. Weekly, microcultures were restimulated with irradiated, autologous peptide-loaded peripheral blood mononuclear cells and expanded in IL-2. Established T cell lines were tested by cytokine release assays using peptide-loaded T2 targets. T cell avidity was measured by cytokine release using targets expressing diminishing concentrations of peptide. Fine specificities were measured using targets loaded with alanine-substituted CAP1 peptide. Tumor recognition was measured using HLA-A*A0201/CAP1-transduced COS tumor targets. Varied responses to CAP1 and CAP1-6D were seen among individuals. The immunogenicity of CAP1 or CAP1-6D was donor dependent. Many T cells recognized one peptide but did not cross-recognize the altered peptide. The avidities of T cell lines were moderate to low, and fine specificities were consistent with a narrow antigen-specific repertoire. CAP1-6D-based immune therapy may not be optimal in some patients with CAP1-specific precursors. The T cell repertoire may be a central contributor to the limited responses seen with CEA-directed immunotherapy to date. Treatment strategies designed to alter or expand the T cell repertoire against CEA should be considered for trials.
Brown
Matthew E
ME
Department of Surgery, University of Chicago, IL, USA.
Miao
Haixi
H
McKee
Mark D
MD
D002272:Carcinoembryonic Antigen / Q000032:analysis / Q000276:immunology* / Q000494:pharmacology; D003429:Cross Reactions; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007376:Interleukin-2 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D009369:Neoplasms / Q000737:chemistry / Q000276:immunology* / Q000628:therapy; D009842:Oligopeptides / Q000032:analysis / Q000276:immunology* / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
C405522:CAP1-6D; D002272:Carcinoembryonic Antigen; D007376:Interleukin-2; D015851:Interleukin-7; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell