Liver sinusoidal endothelial cells contribute to CD8 T cell tolerance toward circulating carcinoembryonic antigen in mice
- 14 October 2012
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 56 (5), 1924-1933
- https://doi.org/10.1002/hep.25844
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 CD44highCD62LhighCD25neg. 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;56:1924–1933)Keywords
This publication has 25 references indexed in Scilit:
- Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and PromotionScience, 2011
- The immunoregulatory mechanisms of carcinoma for its survival and developmentJournal of Experimental & Clinical Cancer Research, 2011
- Regulatory T cells in tumor immunityInternational Journal of Cancer, 2010
- Development of a Multimarker Assay for Early Detection of Ovarian CancerJournal of Clinical Oncology, 2010
- Myeloid-Derived Suppressor Cells: Linking Inflammation and CancerPublished by The American Association of Immunologists ,2009
- The TGF-β paradox in human cancer: an updateFuture Oncology, 2009
- Indoleamine 2,3‐dioxygenase in T‐cell tolerance and tumoral immune escapeImmunological Reviews, 2008
- Carcinoembryonic Antigen in the Staging and Follow-up of Patients with Colorectal CancerCancer Investigation, 2005
- Mini‐review: The nuclear protein HMGB1 as a proinflammatory mediatorEuropean Journal of Immunology, 2004
- MHC antigens and tumor escape from immune surveillanceAdvances in Cancer Research, 2001