HLA-G expression and role in advanced-stage classical Hodgkin lymphoma

Abstract

Non-classical human leucocyte antigen (HLA)-G class I molecules have an important role in tumor immune escape mechanisms. We investigated HLA-G expression in lymphonode biopsies taken from 8 controls and 20 patients with advanced-stage classical Hodgkin lymphoma (cHL), in relationship to clinical outcomes and the HLA-G 14-basepair (14-bp) deletion-insertion (del-ins) polymorphism. Lymphnode tissue sections were stained using a specific murine monoclonal HLA-G antibody. HLA-G protein expression was higher in cHL patients than controls. In the group of PET-2 positive (positron emission tomography carried out after 2 cycles of standard chemotherapy) patients with a 2-year progression-free survival rate (PFS) of 40%, we observed high HLA-G protein expression within the tumor microenvironment with low expression on Hodgkin and Reed-Sternberg (HRS) cells. Conversely, PET-2 negative patients with a PFS of 86% had higher HLA-G protein expression levels on HRS cells compared to the microenvironment. Lower expression on HRS cells was significantly associated with the HLA-G 14-bp ins/ins genotype. These preliminary data suggest that the immunohistochemical pattern of HLA-G protein expression may represent a useful tool for a tailored therapy in patients with cHL, based on the modulation of HLA-G expression in relation to achievement of negative PET-2.These preliminary data suggest that the immunohistochemical pattern of HLA-G protein expression may represent a useful tool for a tailored therapy in patients with cHL, based on the modulation of HLA-G expression in relation to achievement of negative PET-2.

Figure 1.

Immunohistochemical staining of HLA-G expression (brown color) in a control (left) and in an advanced-stage cHL patient (right) with a larger number of immunopositive reactive cells and a Reed-Sternberg cell (RS). Scale bars: 50 μm.

Figure 2.

HLA-G expression (brown color) according to PET-2 results. Left: a 45 year-old female with negative PET-2. The patient shows low HLA-G protein expression in lymphocytes; conversely, Reed-Srernberg cells (RS) are stained. Right: HLA-G is more expressed in reactive cells then in Reed-Srernberg cells (RS) in a 37 year-old female with positive PET 2. Scale bars: 50 μm.

Figure 3.

HLA-G expression (brown color) according to the HLA-G 14-bp polymorphism in cHL. Left: a 32 year-old female, homozygous for the 14-bp insertion (in/in). Right: a 46 year-old male, homozygous for the 14-bp deletion (del/del). HLA-G expression is higher in the del/del patient sample. RS, Reed-Sternberg cells. Scale bars: 50 μm.

Figure 4.

a) Possible dual role of HLA-G expression in HRS cells and the tumor microenvironment in classical Hodgkin lymphoma; adapted from: Rouas-Freiss et al., J Immunol Res 2014;2014:359748. b) HLA-G balancing model, promoting tumor immune-escape. c) HLA-G balancing model, promoting anti-tumor activity.