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. 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

Tumor regulation of the tissue environment in the liver

“…Tolerance towards common antigens associated with colorectal cancer, like carcinoembryonic antigen, does also occur in human patients, representing a liver-specific tumor immune escape mechanism (Hochst, et al, 2012). The endocytotic uptake of tumor-associated antigens by LSEC is, at least partially, mediated by mannose receptors on LSEC.…”

“…For example, LSEC sample the blood, which contains nutrients and microbial antigens from the gut, and induce T cell tolerance to antigens to which no preexisting immunity exists (Schurich, et al, 2009). However, the same mechanism also leads to hepatic tolerance towards tumor-associated antigens and enables metastatic spread into the liver (Arteta, et al, 2010; Hochst, et al, 2012), illustrating one non-immune cell-mediated mechanism of tumor immune escape that is unique to the liver.…”

Bioreactor technologies to support liver function in vitro

“…Unusual cell types that act as antigen-presenting cells (APCs) exist in the liver and include resident hepatic cells such as sinusoidal endothelial cells, Kupffer cells, and stellate cells [25]. Such antigen presentation usually results in tolerance characterized by CD8+ T cells with low effector functions, such as IFN-gamma production [25,26]. Additionally, the threshold of innate immune response is higher within the hepatic microenvironment.…”

Hepatic immune regulation by stromal cells

“…An autocrine co-stimulatory factor, IL-2 production predominates over PD-L1-mediated signaling [17]. Intriguingly, the non-responsiveness induced in T cells by LSECs could be a possible target for cancer immunotherapy, because LSECs are capable of cross-presenting circulating tumor antigens, thereby inducing non-responsive antigen-specific CD8 + T cells through the PD-1/PD-L1 pathway [19].…”