Soluble human leukocyte antigen-G serum level is elevated in melanoma patients and is further increased by interferon-? immunotherapy

Abstract

BACKGROUND The nonclassic human major histocompatibility complex class I antigens human leukocyte antigen (HLA)–G are proposed to protect tumor cells from natural killer cell lysis. In the current study, the authors measured soluble HLA‐G molecules (sHLA‐G) in serum from patients with malignant melanoma. METHODS Soluble HLA‐G was determined in serum samples of 190 melanoma patients with various stages of disease, with or without current therapy including interferon (IFN)–α and different cytostatics in comparison to 126 healthy controls by using a two‐step enzyme‐linked immunoadsorbent assay. RESULTS Serum sHLA‐G was significantly (P < 0.0005) elevated in melanoma patients (mean ± standard error of the mean [SEM] = 41.95 ± 2.15 ng/mL) compared with healthy controls (mean ± SEM = 22.92 ± 1.51 ng/mL). Univariate analysis revealed a correlation of sHLA‐G serum level with advanced stages of disease (P < 0.001) and tumor load (P < 0.05). Patients undergoing immunotherapy with IFN‐α (n = 31) showed an increased serum sHLA‐G (mean ± SEM = 62.05 ± 7.58 ng/mL; P < 0.0005), whereas other treatment regimens (n = 24) did not influence sHLA‐G serum concentrations. Multivariate analysis revealed treatment with IFN‐α as the only impact factor for elevated serum sHLA‐G, lacking any correlation with stage of disease or tumor burden. Furthermore, IFN‐α was found to upregulate HLA‐G cell surface expression on circulating monocytes. sHLA‐G serum level was not associated with recurrence free or overall survival. CONCLUSIONS This study shows increased sHLA‐G serum concentrations in melanoma patients and additional enhancement upon treatment with IFN‐α. The level of serum sHLA‐G, however, had no negative impact on patients' prognosis. Cancer 2001;92:369–76. © 2001 American Cancer Society.

Switch ofHLA-G alternative splicing in a melanoma cell line causes loss of HLA-G1 expression and sensitivity to NK lysis

“…13,39,[48][49][50][51] Such an observation deserves particular attention in the context of IFN-based immunotherapy or anti-tumor chemotherapy using demethylating drugs such as decitabine in melanoma patients whose immune system may be inhibited by the boosted expression of HLA-G1. 6,7 Interestingly, in our study, the HLA-G switch from HLA-G1 to HLA-G2 was strong enough to prevent reexpression of HLA-G1 mRNA and protein even following treatment with cytokines and DNA demethylating agent.…”

“…1 HLA-G is normally absent on healthy tissues except trophoblast, 2 thymus 3 and cornea. 4 Interestingly, both HLA-G transcription and protein expression are up-regulated on various tumors cells, as demonstrated in biopsies from patients with melanoma, [5][6][7] breast cancer, 8 renal carcinoma, 9,10 primary cutaneous lymphoma, 11 lung cancer, 12 glioma, 13 epithelial cutaneous malignant lesions 14 and colorectal cancer. 15 .…”

“…Moreover, the immunotolerant role of HLA-G has been emphasized by its involvement in the resistance to IFN-based therapies that is observed in some melanoma patients. 6,7 In contrast to these data obtained with surgically removed tumor lesions, the detection of HLA-G on in vitro established tumor cell lines has been mainly unsuccessful (reviewed in 1). To date, only a few tumor cell lines, other than choriocarcinoma cell lines, have been found to express cell-surface HLA-G: 4 renal carcinoma cell lines, 9,16,17 4 glioma cell lines 13 and 9 short-term ovarian carcinoma cell lines.…”

Soluble HLA-G: Are they clinically relevant?

“…Although sHLA-G up-regulation was positively correlated with advanced stage of the disease and with tumor load, no correlation with patient prognosis was identified [60]. Treatment with IFN-α was associated with increased serum levels of sHLA-G, irrespective of disease stage and tumor load.…”

“…Treatment with IFN-α was associated with increased serum levels of sHLA-G, irrespective of disease stage and tumor load. On the other hand the increased sHLA-G serum level was found to be related to IFN-α induced up-regulation of surface HLA-G on peripheral blood monocytes [60].…”