title: Liver sinusoidal endothelial cells contribute to CD8 T cell tolerance toward circulating carcinoembryonic antigen in mice.
abstract: Immunity against cancer is impeded by local mechanisms promoting development of tumor-specific T cell tolerance, such as regulatory T cells, myeloid-derived suppressor cells, or immunosuppressive factors in the tumor microenvironment. The release of soluble antigens, such as carcinoembryonic antigen (CEA) from colorectal carcinoma (CRC) cells, has been investigated for diagnostic purposes, but not for its immunological consequences. Here, we address the question of whether soluble CEA influences tumor-specific immunity. Mice were injected with soluble CEA protein, and CEA-specific CD8 T cells were analyzed for their phenotype and functionality by means of restimulation ex vivo or antitumor efficacy in vivo. We furthermore characterized the CD8 T cell population in peripheral blood mononuclear cell (PBMCs) from healthy donors and colorectal carcinoma patients. In mice, circulating CEA was preferentially taken up in a mannose receptor-dependent manner and cross-presented by liver sinusoidal endothelial cells, but not dendritic cells, to CD8 T cells. Such systemically circulating CEA promoted tolerization of CEA-specific CD8 T cells in the endogenous T cell repertoire through the coinhibitory molecule B7H1. These CD8 T cells were not deleted but were rendered nonresponsive to antigen-specific stimulation and failed to control growth of CEA-expressing tumor cells. These nonresponsive CD8 T cells were phenotypically similar to central memory T cells being CD44(high) CD62L(high) CD25(neg) . We found T cells with a similar phenotype in PBMCs of healthy donors and at increased frequency also in patients with colorectal carcinoma.
  
  
  CONCLUSIONS
  Our results provide evidence for the existence of an unrecognized tumor immune escape involving cross-presentation of systemically circulating tumor antigens that may influence immunotherapy of cancer.
authors.affiliation: Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Höchst
authors.forename: Frank A
authors.initials: FA
authors.lastname: Schildberg
authors.forename: Jan
authors.initials: J
authors.lastname: Böttcher
authors.forename: Christina
authors.initials: C
authors.lastname: Metzger
authors.forename: Sebastian
authors.initials: S
authors.lastname: Huss
authors.forename: Andreas
authors.initials: A
authors.lastname: Türler
authors.forename: Markus
authors.initials: M
authors.lastname: Overhaus
authors.forename: Andreas
authors.initials: A
authors.lastname: Knoblich
authors.forename: Berthold
authors.initials: B
authors.lastname: Schneider
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Pantelis
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.forename: Jörg C
authors.initials: JC
authors.lastname: Kalff
authors.forename: Percy
authors.initials: P
authors.lastname: Knolle
authors.forename: Linda
authors.initials: L
authors.lastname: Diehl
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D060890:B7-H1 Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000097:blood / Q000276:immunology*; D002277:Carcinoma / Q000097:blood / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000097:blood / Q000276:immunology*; D042783:Endothelial Cells / Q000276:immunology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008099:Liver / Q000276:immunology*; D018655:Lymphocyte Count; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype
chemical_list: D060890:B7-H1 Antigen; D002272:Carcinoembryonic Antigen; D018960:Hyaluronan Receptors; D053645:Interleukin-2 Receptor alpha Subunit; D019041:L-Selectin