HLA-F expression is a prognostic factor in patients with non-small-cell lung cancer
Introduction
During cancer immune editing, host immune system plays in eliminating tumor cells and in facilitating the emergence of their immunoresistant variants [1]. Partially or totally down-regulate the expression of human leukocyte antigen (HLA) class I antigens is one of the most common events in the tumor progression [2]. A variety of altered HLA phenotypes have been defined in human tumors, including HLA total loss, HLA haplotype loss, HLA-specific locus down-regulation, HLA allelic losses, and a combination of these phenotypes. However, while the loss of HLA class I expression enables cancer cells to escape from CD8+ T cell recognition, it renders them highly vulnerable to natural killer (NK) cell-mediated lysis [3], [4]. Upregulation of tolerogenic non-classical HLA class I molecules such as HLA-G and HLA-E may therefore be an alternative strategy for tumors to acquire protection against both NK and T cells [5], [6].
Unlike the very highly polymorphic classical HLA class I antigens, the nonclassical HLA class I molecules HLA-E, HLA-F, and HLA-G have a limited polymorphism and display a restricted expression pattern [7], [8]. HLA-E and HLA-G have been shown to be able to present peptide, whereas HLA-F is expressed as an empty intracellular molecule [9], [10], [11], [12]. Among non-classical HLA class I molecules, HLA-G does not only show the most restricted tissue expression, but also the most complex splicing pattern which could yield seven alternatively spliced isoforms including membrane-bound HLA-G1–HLA-G4 and soluble HLA-G5–HLA-G7 proteins [13].
To date, intensive studies on the biological characteristics and clinical relevance of HLA-G and HLA-E in malignancies have been carried out [6], [14]. Previous studies revealed that HLA-G is a potent immunosuppressive molecule which could render direct inhibitory effects on NK cells, dendritic cell (DC)s, and T cells and long-term tolerogenic indirect effect by inducing regulatory T cells (Treg) [15]. Expression of HLA-G in normal tissues is very limited, however, aberrant ectopic expression of this molecule was observed in nearly 30 types of malignancies including leukemia and solid tumors and its relevance to prognosis has been intensively investigated [6]. HLA-E expression by tumor cells has been recently reported in several types of human cancers such as lymphomas, ovarian carcinomas, gliomas, colon cancer, and melanomas [16], [17], [18], [19], [20]. Because of its capacity to bind to the inhibitory CD94/NKG2A receptor expressed by NK cells and a subset of CD8+αβ and γδT cells, HLA-E expression by neoplastic cells might favor tumor cell escape from immune surveillance [21]. Indeed, a recent report indicated that HLA-E expression was associated with poor relapse-free period in classical HLA I antigen negative breast cancer patients [22].
HLA-F has recently only begun to be studied in earnest, and a few reports on the protein expression have appeared so far. HLA-F was not surface expressed on most cell lines that contained intracellular protein, while HLA-F was expressed on the surface of B and some monocyte cell lines and in vivo on extravillous trophoblasts that had invaded the maternal decidua [11], [23]. Further examination of peripheral blood leukocytes demonstrated intracellular HLA-F protein expression in all resting lymphocyte subsets, including B and T lymphocytes, NK, and monocyte cells, and HLA-F surface expression was upregulated upon activation for all cell types [24]. Furthermore, cytoplasm HLA-F expression was found in cell lines established from transitional cell carcinomas of the bladder, from glioblastoma and liver cancer [25]. It should be noted that HLA-F/β2m-tetramers could bind to the immune inhibitory receptors ILT-2 and ILT-4, indicating potential role of HLA-F in regulating the functions of immune cells [26]. In addition, anti-HLA-F antibody in sera from patients suffering from liver, stomach, pancreatic and other cancers was addressed with potential diagnostic value [27]. However, knowledge on HLA-F in cancer is scarce and its function remains enigmatic.
In this study, HLA-F expression in non small-cell lung cancer (NSCLC) lesions was analyzed with immunohistochemistry, and its correlation to clinical parameters were evaluated.
Section snippets
Study population
Tumor lesions and adjacent normal lung tissues were obtained from 83 patients with NSCLC diagnosed and treated consecutively between February 13, 2005 and December 30, 2009 at Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical College. Patient data including age, gender, date of initial diagnosis, histological diagnosis, tumor grade, clinical stage and date of death from NSCLC or last follow-up were documented. Histological diagnosis and tumor stage were determined in
HLA-F expression in primary NSCLC lesions
Overall, 24.1% (20/83) tumor lesions were classified as HLA-F positive (Table 1). In the malignant tumor sections, the intensity of staining varied from tumor to tumor and from one area to another within the same tumor. Heterogeneous staining was noted in all HLA-F positive NSCLC lesions. Some tumors showed focal patchy positive staining, and others displayed uniform staining pattern in tumor nests. Positive staining was observed in both the cell membrane and the sub-membranous cytoplasm
Discussion
In this study, HLA-F expression was observed in 24.1% (20/83) of the primary NSCLC lesions, but not in corresponding adjacent non-tumorous lung tissues. We found that HLA-F expression in NSCLC was not associated with the clinical parameters such as grade of tumor differentiation and disease stage. However, HLA-F positive NSCLC patients were of poor prognosis and HLA-F expression could be an independent prognostic factor for NSCLC patients.
Geraghty et al. first identified the HLA-F gene and
Conclusion
Our study, for the first time, revealed that HLA-F expression is associated with patient survival and could be an independent prognostic indicator in NSCLC patients. However, the biological functions and clinical relevance of HLA-F expression in normal tissues or in malignant samples remains more investigations.
Conflict of interest statement
None declared.
Acknowledgements
This work was supported by Zhejiang Provincial program for the cultivation of high-level innovative health talents, and by the grants from Science and Technology Bureau of Zhejiang Province (2008C33013 and 2009C33147) and Zhejiang Provincial Natural Science Foundation of China (Y2101323).
References (33)
Immune surveillance: a balance between protumor and antitumor immunity
Curr Opin Genet Dev
(2008)- et al.
Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity
Adv Immunol
(2006) - et al.
HLA class I antigen expression in malignant cells: why does it not always correlate with CTL-mediated lysis?
Curr Opin Immunol
(2004) - et al.
Immune-refractory cancers and their little helpers – an extended role for immunetolerogenic MHC molecules HLA-G and HLA-E?
Semin Cancer Biol
(2007) - et al.
Functions of nonclassical MHC and non-MHC-encoded class I molecules
Curr Opin Immunol
(1999) - et al.
Nonclassical HLA-G molecules are classical peptide presenters
Curr Biol
(1996) - et al.
Human leukocyte antigen-G polymorphism in relation to expression, function, and disease
Hum Immunol
(2009) - et al.
HLA-G-dependent suppressor cells: diverse by nature, function, and significance
Hum Immunol
(2008) - et al.
Genome-wide association study reveals multiple nasopharyngeal carcinoma-associated loci within the HLA region at chromosome 6p21.3
Am J Hum Genet
(2009) - et al.
HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance
Oncogene
(2008)