Elsevier

Human Immunology

Volume 71, Issue 5, May 2010, Pages 489-495
Human Immunology

Prognostic relevance of soluble human leukocyte antigen–G and total human leukocyte antigen class I molecules in lung cancer patients

https://doi.org/10.1016/j.humimm.2010.02.015Get rights and content

Abstract

The aim of this study was to determine the prognostic significance of soluble human leukocyte antigen (HLA) class I (sHLA-I) and HLA-G molecules in lung cancer patients. A total of 23 small-cell lung cancer (SCLC) and 114 non–small-cell lung cancer (NSCLC) patients, including 55 adenocarcinoma, 46 squamous cell carcinoma (SCC), and 13 patients with undifferentiated carcinoma, were prospectively enrolled. Levels of sHLA-G and sHLA-I were analyzed by specific enzyme-linked immunosorbent assay. Median levels of sHLA-G and sHLA-I were significantly increased in patients compared with controls (34 ng/ml [3.6–160] vs 14 ng/ml [0–98], p < 0.0001; 2580 ng/ml [749–5770] vs 1370 ng/ml [274–2670], p < 0.0001, respectively). Regarding the different subgroups, patients with NSCLC or SCLC showed increased sHLA-I levels, whereas sHLA-G was exclusively elevated in NSCLC, especially in patients with SCC. Patients with sHLA-I<2800 ng/ml (p = 0.008) or sHLA-G<40 ng/ml (p = 0.073) showed prolonged overall survival (OS). Using these cut-offs in patients with SCC, a pronounced prognostic significance for sHLA-G (p = 0.003) and sHLA-I (p = 0.004) was observed for the prediction of OS. Here, multivariate analysis confirmed sHLA-G and sHLA-I in addition to disease stage as independent prognostic factors. The prognostic power was further enhanced by combining the two factors and comparing the OS of patients with low sHLA-I and low sHLA-G against the remaining ones. In conclusion, plasma levels of sHLA-G and sHLA-I are potent predictors for OS in lung cancer patients.

Introduction

Lung cancer is the leading cause of cancer mortality, resulting in more than 160,000 deaths annually in the United States. Surgery, radiotherapy, and medical treatment using classical chemotherapeutic drugs or target therapies are standard treatments for lung cancer patients. In addition, certain immune therapeutic strategies have been shown in clinical trials to elicit or strengthen a cellular immune response against the tumor [1], [2]. The limited effectiveness of such approaches in lung cancer may indicate that mechanisms are operative in vivo, enabling tumor cells to escape from immunosurveillance.

Among various molecules implicated in immune escape mechanisms of tumor cells, the nonclassical human leukocyte antigen–G (HLA-G) seems to be one of the most powerful molecules for the suppression of the innate and/or adaptive immune response by multiple pathways of the immune system [3]. In contrast to classical HLA class I molecules, HLA-G displays a limited polymorphism but can exists in seven different isoforms known to be expressed as membrane-anchored molecules (HLA-G1, G2, G3, and G4 isoforms) and as secreted soluble ones (HLA-G5, G6, and G7 isoforms) [4]. With regard to function, HLA-G molecules suppress the effector functions of T cells and natural killer (NK) cells by the engagement with immunoglobulin-like transcript (ILT) receptors ILT2 (LILRB1/CD85j), ILT4 (LILRB2/CD85d), CD8 α-chain, killer immunoglobulinlike receptor 2DL4 (KIR2DL4/ CD158d), and CD160 [5], [6], [7]. The interaction of ILT2 and ILT4 with HLA-G on dendritic cells (DC) results in the downregulation of co-stimulatory molecules as well as in the downregulation of HLA class II antigens. Such modified DC enable the differentiation of anergic and immunosuppressive CD4- and CD8-positive T cells [8]. Interestingly, the modulation of DC differentiation by HLA-G and ILT4 requires the IL-6 STAT3 signaling pathway [9]. As soluble and membrane-anchored HLA-G exhibit the same receptor specificity, both types of molecules are potent regulators for the innate and acquired cellular immune response. In view of the functional properties, it is not surprising that, under physiologic conditions, HLA-G expression is confined to immune privileged sites, such as fetal tissue, cornea, pancreatic islets, and adult thymic medulla, where it plays a crucial role in mediating immunotolerance [3]. Nevertheless, traces of HLA-G can be found in blood cells [10] and as soluble molecules in the blood of healthy individuals [11]. In recent years, a growing number of studies have documented an aberrant expression of membrane-anchored or soluble HLA-G molecules in cancer [3], [12]. In addition, clinical studies have often found an association of high levels of membrane-anchored or soluble HLA-G molecules with a shortened overall and/or progression-free survival of patients [12], [13], [14], [15], [16], [17], [18]. In peripheral blood, the most abundant soluble HLA molecules are the classical class I molecules. With regard to functions, both types of soluble molecules, the classical HLA-I and the nonclassical HLA-G molecules, exhibit strong immunosuppressive properties; soluble HLA-G (sHLA-G) and soluble classical HLA-I molecules (sHLA-I) are able to induce apoptosis in activated CD8+ T lymphocytes or NK cells through ligation with the CD8 coreceptor [19], [20], [21]. Although the classical HLA class I molecule displays a lower affinity to ILT-2 and ILT-4 than does HLA-G, both molecules are able to induce the inhibition of T and NK cell effector functions by interaction with these inhibitory receptors [22], [23]. The clinical relevance of sHLA-I was studied for patients with pancreatic cancer, malignant lymphoma, acute myeloid leukemia, and multiple myeloma. Increased serum sHLA-I levels of the patients were associated with a poor prognosis [24], [25], [26], [27], [28], [29], [30]. A recent report revealed that, compared with controls, lung cancer patients with metastatic disease had significantly increased levels, whereas patients with localized disease exhibited diminished levels [31]. By contrast, downregulation or loss of HLA class I surface expression is frequently found in malignancy and has been associated with an undifferentiated cell phenotype and aneuploid cancer cells in lung cancer [32]. Kikuchi et al. demonstrated that downregulation of HLA-I on lung cancer cells was an independent poor prognostic factor for overall survival [33]. It is thought that loss of HLA-I expression on tumor cells is a mechanism for tumor cells to escape immunosurveillance. In view of this, we studied the clinical relevance of sHLA-G in comparison with the total amount of soluble HLA class I in various subgroups of lung cancer patients. To this end, plasma samples of lung cancer patients were prospectively collected and tested for their content of sHLA-I and sHLA-G by specific ELISA formats. The results obtained were correlated with clinical parameters, and their relevance for the prognosis of the patients was investigated.

Section snippets

Patients and procedure

From September 2001 to December 2007, plasma samples were collected from 137 lung cancer patients (95 males and 42 female), including 23 patients with small-cell lung cancer (SCLC) and 114 patients with non–small-cell lung cancer (NSCLC). The patients' characteristics are summarized in Table 1. Only patients with histologically or cytologically confirmed diagnoses of lung cancer were included in this study. Patients who underwent chemotherapy within 3 months before blood sampling or patients on

Total sHLA-I and sHLA-G plasma levels in lung cancer patients

In lung cancer patients (n = 137), the plasma levels (median [range]) of sHLA-G and total sHLA-I were significantly increased compared with those in healthy controls (34 ng/ml [3.6–160] vs 14 ng/ml [0–98], p < 0.0001; 2580 ng/ml [749–5770] vs 1370 ng/ml [274–2670], p < 0.0001, respectively). Subgroup analysis revealed that patients with NSCLC and with SCLC exhibit significantly increased levels of sHLA-I, whereas sHLA-G was predominantly elevated in patients with NSCLC (Fig. 1). Patients with

Discussion

Both soluble HLA-G and soluble classical HLA class I molecules are able to suppress the innate and the adaptive immune system. Because of these functional properties, both molecules appear to be promising markers for the prediction of overall or progression-free survival in cancer patients. So far a comparative analysis of these two markers has been performed for patients with multiple myeloma and malignant lymphoma [25], [27], [30]. Here, increased serum levels of sHLA-I and sHLA-G were

References (46)

  • J.J.Shih IeM. Sheu

    Clinical and biological significance of HLA-G expression in ovarian cancer

    Semin Cancer Biol

    (2007)
  • S.R. Ye et al.

    Human leukocyte antigen G expression: as a significant prognostic indicator for patients with colorectal cancer

    Mod Pathol

    (2007)
  • G.M. Spaggiari et al.

    Soluble HLA class I molecules induce natural killer cell apoptosis through the engagement of CD8: evidence for a negative regulation exerted by members of the inhibitory receptor superfamily

    Blood

    (2002)
  • A. Naji et al.

    Soluble HLA-G and HLA-G1 expressing antigen-presenting cells inhibit T-cell alloproliferation through ILT-2/ILT-4/FasL-mediated pathways

    Hum Immunol

    (2007)
  • M. Albitar et al.

    Clinical relevance of soluble HLA-I and beta2-microglobulin levels in non-Hodgkin's lymphoma and Hodgkin's disease

    Leuk Res

    (2007)
  • T. Shimura et al.

    Clinical significance of soluble form of HLA class I molecule in Japanese patients with pancreatic cancer

    Hum Immunol

    (2001)
  • M. Nocito et al.

    Increased soluble serum HLA class I antigens in patients with lymphoma

    Hum Immunol

    (1997)
  • P. Schutt et al.

    The clinical significance of soluble human leukocyte antigen class-I, ICTP, and RANKL molecules in multiple myeloma patients

    Hum Immunol

    (2008)
  • K.A. Pfeiffer et al.

    Soluble HLA levels in early pregnancy after in vitro fertilization

    Hum Immunol

    (2000)
  • M. Urosevic et al.

    HLA-G and IL-10 expression in human cancer—different stories with the same message

    Semin Cancer Biol

    (2003)
  • C. Pangault et al.

    Lung macrophages and dendritic cells express HLA-G molecules in pulmonary diseases

    Hum Immunol

    (2002)
  • F. De Vita et al.

    Serum interleukin-10 levels as a prognostic factor in advanced non-small cell lung cancer patients

    Chest

    (2000)
  • M. Urosevic et al.

    Human leukocyte antigen G up-regulation in lung cancer associates with high-grade histology, human leukocyte antigen class I loss and interleukin-10 production

    Am J Pathol

    (2001)
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