Impairment of natural killer cell and dendritic cell functions by the soluble form of MHC class I-related chain A in advanced human hepatocellular carcinomas
Introduction
Human hepatocellular carcinoma (HCC) has the unique characteristic of a high risk of development from chronic inflammatory liver diseases. Despite recent advances in new therapeutic modalities, a significant number of HCC show frequent recurrence and progression to an advanced stage with few curative options [1]. In this regard, the identification and manipulation of molecules that are specifically present in advanced HCC may offer new strategies for improving and broadening therapeutic options.
Natural killer (NK) cells are a major component of innate lymphocytes that predominantly reside in the liver [2], and play a critical role in innate resistance against tumors [3], [4]. In addition, recent studies have revealed that NK cells can modulate the functions of dendritic cells (DC), the major sentinel between innate and adaptive immunity [5], [6]. Therefore, NK cells may also affect the magnitude and direction of adaptive immune responses against tumors. NK cell functions are regulated by a balance of negative and positive signals, which are mediated by inhibitory and activating receptors; the former includes killer cell immunoglobulin-like receptors (KIRs) and C-type lectin-like molecules, such as CD94 and NKG2A/E, and the latter includes the NKG2D activating receptor [7], [8]. A stress-inducible MHC class I-related chain A (MICA) was recently identified as a human ligand of NKG2D [9]. MICA is expressed in many carcinoma cells such as in lung, breast, ovary, prostate, colon cancer, but is usually absent from normal tissue [10], [11]. This raises the possibility of MICA being an important ‘on’ signal for NK cell-mediated innate immune surveillance against tumor cells. A tumor-specific expression pattern of MICA has also been observed in human HCC, and NK cells recognize hepatoma cells via MICA-NKG2D interaction [12]. These findings suggest that MICA-NKG2D may serve as an efficient innate pathway of immune surveillance against HCC.
Recent studies have suggested that MICA is released as a soluble form from the cell surface of tumor cells and can be detected in gastrointestinal malignancy, prostate cancer and leukemia [11], [13], [14], [15], [16]. In addition, the soluble form of MICA (sMICA) was found to sequester NKG2D in the cytoplasm and to inhibit cell-surface NKG2D expression and NKG2D-mediated effector functions of immune cells in progressive malignant tumors [11], [13], [15] and rheumatoid arthritis [17]. Therefore, sMICA may represent one of the factors involved in tumor evasion of host immunity. However, definitive evidence is still lacking as to whether these mechanisms can also be applied to human HCC.
In the present study, we investigated the presence of sMICA in patients with HCC and its function in NK cell activation in human HCC. We also elucidated the role of sMICA on the NK cell-mediated functional regulation of DC.
Section snippets
Subjects
Twenty six patients with HCC, 15 patients with chronic hepatitis C, 9 patients with chronic hepatitis B and 10 healthy individuals were enrolled in this study after informed consent had been obtained. The profiles of patients with HCC are summarized in Table 1. The classification of HCC by tumor node metastasis (TNM) staging [18] was based on diagnostic modalities such as computed tomography and magnetic resonance imaging. Serum levels of alpha-fetoprotein (AFP) were measured using the
sMICA was preferentially released from patients with advanced HCC
We investigated the serum levels of sMICA in 26 patients with HCC of various progression grades, 24 patients with chronic hepatitis (CH) due to HCV or HBV infection and 10 healthy individuals. Significant amounts of sMICA were detected in sera from 11 of the 26 patients with HCC. In contrast, sMICA was not detected in sera from CH patients or healthy individuals except for five cases with marginal positivity (Table 1 and Fig. 1A). These results suggested that sMICA could be detected in a
Discussion
We previously reported that MICA is expressed in surgically removed tumor tissues with HCC and marks hepatoma cells for recognition of NK cells by activating the immunoreceptor NKG2D [12]. In the present study, significant levels of sMICA were detected in a subset of HCCs. On the other hand, it was only detected at marginal levels in patients with chronic hepatitis C and B, the underlying diseases for HCC development. This clearly is in contrast with the cases of other chronic inflammatory
Acknowledgements
This work was supported by a Grant-in-Aid from the Ministry of Culture, Sports, Science and Technology of Japan, a Grant-in-Aid for Research on Hepatitis and BSE from the Ministry of Health, Labor and Welfare of Japan, and the 21st Century Center of Excellence program of the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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