Universität zu Köln

Hoechst, Bastian, Schildberg, Frank A., Boettcher, Jan, Metzger, Christina, Huss, Sebastian, Tuerler, Andreas, Overhaus, Markus, Knoblich, Andreas, Schneider, Berthold, Pantelis, Dimitrios, Kurts, Christian, Kalff, Joerg C., Knolle, Percy and Diehl, Linda (2012). Liver sinusoidal endothelial cells contribute to CD8 T cell tolerance toward circulating carcinoembryonic antigen in mice. Hepatology, 56 (5). S. 1924 - 1934. HOBOKEN: WILEY-BLACKWELL. ISSN 0270-9139

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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 receptordependent 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. (HEPATOLOGY 2012;56:19241933)

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hoechst, Bastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Schildberg, Frank A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boettcher, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Metzger, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Huss, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Tuerler, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Overhaus, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Knoblich, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, Berthold UNSPECIFIED UNSPECIFIED UNSPECIFIED Pantelis, Dimitrios UNSPECIFIED UNSPECIFIED UNSPECIFIED Kurts, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Kalff, Joerg C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Knolle, Percy UNSPECIFIED UNSPECIFIED UNSPECIFIED Diehl, Linda UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-480515
DOI:	10.1002/hep.25844
Journal or Publication Title:	Hepatology
Volume:	56
Number:	5
Page Range:	S. 1924 - 1934
Date:	2012
Publisher:	WILEY-BLACKWELL
Place of Publication:	HOBOKEN
ISSN:	0270-9139
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CROSS-PRESENTATION; COLORECTAL-CANCER; LEADS; IMMUNITY; ESCAPE Multiple languages Gastroenterology & Hepatology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48051