HLA‐G protein expression as a potential immune escape mechanism in classical Hodgkin’s lymphoma

Abstract

Classical Hodgkin's lymphoma (cHL) is characterized by the presence of an abundant reactive infiltrate, lacking effective cytotoxic responses. Especially in Epstein-Barr virus (EBV)-negative cHL, the neoplastic Hodgkin-Reed-Sternberg (HRS) cells have lost protein expression of major histocompatibility complex (MHC) class I, enabling escape from cytotoxic T lymphocyte (CTL) responses. However, downregulation of MHC class I generally induces natural killer (NK) cell activation. The paucity of NK cells in the reactive infiltrate of cHL and the systemic NK cell deficiency observed in cHL patients led us to investigate the expression of human leukocyte antigen (HLA)-G, which is known to inhibit NK-cell- and CTL-mediated cytotoxicity. By immunohistochemistry, HLA-G protein was expressed by HRS cells in 54% (95/175) of cHL cases. This expression was associated with absence of MHC class I on the cell surface of HRS cells (P < 0.001) and EBV-negative status (P < 0.001). Previously, genetic markers located in the proximity of the HLA-A and HLA-G genes had been shown to be associated with susceptibility to EBV-positive cHL. In the present study, these markers associated with MHC class I protein expression but not with presence of HLA-G. Our results suggest that induction of HLA-G protein expression in HRS cells contributes to the modulation of immune responses observed in cHL.

HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma

“…In this scenario, we would envisage a protective response directed against EBV antigens expressed by Hodgkin/Reed-Sternberg cells, i.e., EBNA1, LMP1, and LMP2. Hodgkin/Reed-Sternberg cells express HLA class I and TAP1/2 and therefore should be able to process antigen for presentation to CTLs (28,29); however, EBV-specific CTLs do not appear to accumulate or expand within tumors (30). Secretion of immunomodulatory cytokines, such as interleukin 10 and transforming growth factor β, and skewing of the infiltrating T cells toward T-helper 2/T-regulatory subsets by CCL17 and galectin 1 could all contribute to a local immunosuppressive effect within tumors (31)(32)(33).…”

Molecular Pathways: Human Leukocyte Antigen G (HLA-G)

“…In addition, the HLA-G protein was found in cases of cutaneous lymphoma (8), in chronic lymphatic leukemia (CLL) with significant increase of serum HLA-G (36-40), in classical Hodgkin lymphoma (cHL; ref. 41), NHL (42), and in multiple myeloma (43). In solid tumors, expression of HLA-G and detection of sHLA-G are heterogeneous.…”

Microenvironment, Crosstalk, and Immune Escape Mechanisms

“…The inhibitory receptors can also be engaged by a nonclassical HLA class I-like molecule known as HLA-G. In about two thirds of HLA class I-negative cHL cases, the HRS cells indeed express HLA-G [ 87 ]. Besides NK cell inhibition, HLA-G might also induce Treg cells and inhibit cytotoxic T cell responses.…”