Expression and Release of HLA-E by Melanoma Cells and Melanocytes: Potential Impact on the Response of Cytotoxic Effector Cells

Abstract

HLA-E are nonclassical MHC molecules with poorly characterized tissue distribution and functions. Because of their capacity to bind the inhibitory receptor, CD94/NKG2A, expressed by NK cells and CTL, HLA-E molecules might play an important role in immunomodulation. In particular, expression of HLA-E might favor tumor cell escape from CTL and NK immunosurveillance. To address the potential role of HLA-E in melanoma immunobiology, we assessed the expression of these molecules ex vivo in human melanoma biopsies and in melanoma and melanocyte cell lines. Melanoma cell lines expressed no or low surface, but significant intracellular levels of HLA-E. We also report for the first time that some of them produced a soluble form of this molecule. IFN-γ significantly increased the surface expression of HLA-E and the shedding of soluble HLA-E by these cells, in a metalloproteinase-dependent fashion. In contrast, melanocyte cell lines constitutively expressed HLA-E molecules that were detectable both at the cell surface and in the soluble form, at levels that were poorly affected by IFN-γ treatment. On tumor sections, a majority of tumor cells of primary, but a low proportion of metastatic melanomas (30–70 and 10–20%, respectively), expressed HLA-E. Finally, HLA-E expression at the cell surface of melanoma cells decreased their susceptibility to CTL lysis. These data demonstrate that HLA-E expression and shedding are normal features of melanocytes, which are conserved in melanoma cells of primary tumors, but become dependent on IFN-γ induction after metastasis. The biological significance of these findings warrants further investigation.

HLA-E upregulation on IFN-γ-activated AML blasts impairs CD94/NKG2A-dependent NK cytolysis after haplo-mismatched hematopoietic SCT

“…IFN-g has earlier been reported to protect ovarian carcinoma and melanoma cells from lysis through a CD94/NKG2A-dependent pathway. 17,22 Similar effects are reported during virus infections. Tomasec et al 23 showed that co-infection of fibroblasts with high amounts of recombinant adenovirus encoding HLA-E and UL40 CVM protein results in increase of HLA-E expression and protection against NK lysis through CD94/NKG2A.…”

HLA-E contributes to an immune-inhibitory phenotype of glioblastoma stem-like cells

“…Under physiological conditions, HLA-E is mainly involved in maternal immune tolerance. HLA-E is abberantly expressed in several tumors like lymphoma (Marin et al, 2003), melanoma (Derre et al, 2006), colon carcinoma (Bianchini et al, 2006), ovarian cancer (Malmberg et al, 2002) and may contribute to immunosuppression in glioblastoma (Mittelbronn et al, 2007;Wischhusen et al, 2005).…”

Therapeutic preparations of IVIg contain naturally occurring anti–HLA-E antibodies that react with HLA-Ia (HLA-A/-B/-Cw) alleles

“…14,15 These observations were extended to the sera of nonalloimmunized males to document that the observed HLA-Ia reactivity in human sera could be due to anti-HLA-E Abs. 13 To ascertain whether immunizing humans with HLA-E would augment anti-HLA-E Abs with HLA-Ia reactivity, we examined sera of melanoma patients immunized with autologous melanoma cells grown in interferon-g (IFN-g), a cytokine known to induce overexpression of HLA-E. [16][17][18] The immunized patients not only showed the augmentation of anti-HLA-E Abs, confirming the immunogenicity of HLA-E in humans, but also showed increased reactivity with HLA-Ia (single antigen) coated onto microbeads. 18 Indeed, the pattern of HLA-Ia reactivity in immunized patients corresponded with the pattern of HLA-Ia reactivities exhibited by some of the anti-HLA-E mAbs.…”