title: Anti-CD40 conditioning enhances the T(CD8) response to a highly tolerogenic epitope and subsequent immunotherapy of simian virus 40 T antigen-induced pancreatic tumors.
abstract: Rapid loss of adoptively transferred tumor-specific CD8(+) T cells (T(CD8)) following Ag recognition in the periphery and their limited accumulation within the tumor stroma reduces the effectiveness of T cell-based immunotherapy. To better understand the role of T(CD8) in the control of autochthonous tumors, we have used mice of the RIP1-Tag4 lineage that develop pancreatic beta cell tumors due to expression of the SV40 large T Ag from the rat insulin promoter. We previously showed that the kinetics of functional T(CD8) tolerance varies toward two distinct epitopes derived from T Ag. Epitope I ((206)SAINNYAQKL(215))-specific T(CD8) are rapidly deleted whereas T(CD8) targeting epitope IV ((404)VVYDFLKC(411)) persist over the lifetime of tumor-bearing animals. In this report, we show that the conditioning of tumor-bearing RIP1-Tag4 mice with agonistic anti-CD40 Ab induces extensive expansion of naive epitope I-specific TCR transgenic (TCR-I) T cells in this tolerogenic environment and delays their loss from the host. In addition, functional TCR-I T cells intensively infiltrate pancreatic tumors, resulting in increased survival of RIP1-Tag4 mice. These results suggest that a similar approach could effectively enhance T cell-based immunotherapies to cancer when targeting other highly tolerogenic epitopes.
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Otahal
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Knowles
authors.forename: Satvir S
authors.initials: SS
authors.lastname: Tevethia
authors.forename: Todd D
authors.initials: TD
authors.lastname: Schell
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000627:therapeutic use; D007108:Immune Tolerance / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D011401:Promoter Regions, Genetic; D051381:Rats
chemical_list: D000952:Antigens, Polyomavirus Transforming; D018984:Epitopes, T-Lymphocyte