Liver sinusoidal endothelial cells contribute to CD8 T cell tolerance toward circulating carcinoembryonic antigen in mice
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Liver sinusoidal endothelial cells contribute to CD8 T cell tolerance toward circulating carcinoembryonic antigen in mice. / Höchst, Bastian; Schildberg, Frank A; Böttcher, Jan; Metzger, Christina; Huss, Sebastian; Türler, Andreas; Overhaus, Markus; Knoblich, Andreas; Schneider, Berthold; Pantelis, Dimitrios; Kurts, Christian; Kalff, Jörg C; Knolle, Percy; Diehl, Linda.
in: HEPATOLOGY, Jahrgang 56, Nr. 5, 11.2012, S. 1924-33.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Liver sinusoidal endothelial cells contribute to CD8 T cell tolerance toward circulating carcinoembryonic antigen in mice
AU - Höchst, Bastian
AU - Schildberg, Frank A
AU - Böttcher, Jan
AU - Metzger, Christina
AU - Huss, Sebastian
AU - Türler, Andreas
AU - Overhaus, Markus
AU - Knoblich, Andreas
AU - Schneider, Berthold
AU - Pantelis, Dimitrios
AU - Kurts, Christian
AU - Kalff, Jörg C
AU - Knolle, Percy
AU - Diehl, Linda
N1 - Copyright © 2012 American Association for the Study of Liver Diseases.
PY - 2012/11
Y1 - 2012/11
N2 - UNLABELLED: 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.CONCLUSION: 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.
AB - UNLABELLED: 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.CONCLUSION: 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.
KW - Animals
KW - Antigen-Presenting Cells
KW - Antigens, CD274
KW - Antigens, CD44
KW - CD8-Positive T-Lymphocytes
KW - Carcinoembryonic Antigen
KW - Carcinoma
KW - Colorectal Neoplasms
KW - Endothelial Cells
KW - Humans
KW - Immune Tolerance
KW - Interleukin-2 Receptor alpha Subunit
KW - L-Selectin
KW - Leukocytes, Mononuclear
KW - Liver
KW - Lymphocyte Count
KW - Mice
KW - Mice, Transgenic
KW - Phenotype
U2 - 10.1002/hep.25844
DO - 10.1002/hep.25844
M3 - SCORING: Journal article
C2 - 22610745
VL - 56
SP - 1924
EP - 1933
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
IS - 5
ER -
