Clinical relevance of soluble HLA-I and β2-microglobulin levels in non-Hodgkin's lymphoma and Hodgkin's disease

Abstract

Plasma levels of beta-2 microglobulin (β2M), a subunit of the human leukocyte antigen-class I (HLA-I) molecule, correlate negatively with outcome in non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). We examined the clinical relevance of soluble HLA-I (sHLA-I) levels in NHL and HD. Sera from consecutive NHL (n = 65) and HD (n = 37) patients were analyzed in a blinded manner. NHL and HD patients had significantly higher levels of sHLA-1 and β2M than control subjects. In NHL patients, sHLA-I levels correlated with clinical behavior in a fashion similar to that of β2M. However, multivariate analysis incorporating β2M, sHLA-I, and international prognostic index (IPI) indicated that NHL patients with elevated (>312.6 μg/100 mL) sHLA-I levels had significantly shorter survival, independent of IPI score as well as β2M. In HD patients, β2M but not sHLA-I levels were associated with clinical behavior. These findings not only establish the role of sHLA-I as an independent tumor marker in NHL that can be used to stratify patients, but also suggest that β2M and sHLA-I may reflect different biological processes in HD and NHL. Further studies are needed to assess whether the immunomodulatory properties of sHLA-I may be responsible for its divergence from β2M as an indicator of clinical behavior in HD.

Introduction

Human leukocyte antigen-class I (HLA-I) molecules are cell–surface-associated proteins expressed on most nucleated cells. HLA-I molecules consist of a 44-kDa α (heavy) chain, encoded by a gene in the major histocompatibility complex on chromosome 6, and a 12-kDa β chain (beta-2 microglobulin (β2M)) encoded by a gene on chromosome 15. Although the heavy chain and β2M genes are located on different chromosomes, their expression is coordinated and cells generally express equal numbers of each subunit. The rate of transcription of both genes increases upon exposure to interferon [1], [2], [3], [4]. Free circulating HLA-I (sHLA-1) as well as β2M can be detected as soluble proteins in serum and plasma. Both β2M and the HLA-I protein may shed from the surface of various cell types [3], [4]. However, it is also possible that the spontaneous turnover of tumor cells results in free circulating β2M and the HLA-I proteins [2]. Both molecules have been investigated as potential disease markers. β2M levels are associated with prognosis in various solid tumors and hematologic malignancies, including multiple myeloma [5], Hodgkin's disease (HD) [6] and chronic lymphocytic leukemia (CLL) [7]. The correlation between β2M levels and disease aggressiveness suggests that soluble β2M may reflect an important biological process that represents tumor mass, immune response to the tumor, or both. The relationship of sHLA with lymphoproliferative disorders is less well established.

sHLA appears to function as an immunomodulator [8]. sHLA levels increase in response to T- and B-cell activation, but not interferon-gamma [9], and are also elevated in patients with evidence of cellular destruction (e.g., autoimmune diseases [10], [11], graft verses host disease [GVHD] [12], acute rejection after solid-organ transplantation [13], viral infection [14], [15], tumor proliferation [16]). In vitro data indicate that increased HLA-I expression on the surface of the tumor cells enhances their susceptibility to cytolytic activity of T-cells. Down-modulation of HLA-I expression reduces the cytolytic effects of the T-cells and may be a mechanism of immune system evasion in some leukemias and solid tumors [17], [18], [19]. This down-regulation seems to be limited to the heavy chain and does not involve β2M [17], [18]. On the other hand, the presence of sHLA-I in circulation induces apoptosis of natural killer cells and plays a role in reducing the cytolytic effects of T-cells by binding to these cells and preventing them from reaching tumor cells [20], [21].

Although increased sHLA-I levels have been reported in patients with NHL [20], [21], the clinical relevance of sHLA measurement in HD and NHL remains unknown. In this study, we measured plasma levels of sHLA-I and β2M in NHL and HD patients to: (1) assess the correlation between these markers; (2) compare their utility in predicting clinical behavior; (3) determine whether these markers provide redundant or complementary prognostic information in NHL and HD.