The 4H84 monoclonal antibody detecting β2m free nonclassical HLA-G molecules also binds to free heavy chains of classical HLA class I antigens present on activated lymphocytes

235

195

Nonclassical HLAs, HLA-E and HLA-G, are known to affect clinical outcome in various tumor types. We examined the clinical impact of HLA-E and HLA-G expression in early breast cancer patients, and related the results to tumor expression of classical HLA class I. Our study population (n = 677) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1995. Tissue microarray sections of arrayed tumor and normal control material were immunohistochemically stained for HLA-E and HLA-G. For evaluation of HLA-E and HLA-G and the combined variable, HLA-EG, a binary score was used. Expression of classical HLA class I molecules was determined previously. HLA-E, HLA-G, and HLA-EG on breast tumors were classified as expression in 50, 60, and 23% of patients, respectively. Remarkably, only in patients with loss of classical HLA class I tumor expression, expression of HLA-E (p = 0.027), HLA-G (p = 0.035), or HLA-EG (p = 0.001) resulted in a worse relapse-free period. An interaction was found between classical and nonclassical HLA class I expression (p = 0.002), suggestive for a biological connection. We have demonstrated that, next to expression of classical HLA class I, expression of HLA-E and HLA-G is an important factor in the prediction of outcome of breast cancer patients. These results provide further evidence that breast cancer is immunogenic, but also capable of evading tumor eradication by the host’s immune system, by up- or downregulation of HLA class Ia and class Ib loci.

Section: Immunohistochemistrymentioning

confidence: 99%

“…The 4H84 Ab has been described to occasionally cross-react with classical HLA class I molecules (27). Therefore, we performed additional immunohistochemical analyses to examine whether this cross-reaction would interfere with our survival results.…”

Section: Correction For Specificity Of Absmentioning

confidence: 99%

HLA-E and HLA-G Expression in Classical HLA Class I-Negative Tumors Is of Prognostic Value for Clinical Outcome of Early Breast Cancer Patients

Kruijf¹,

Sajet²,

Nes³

et al. 2010

235

195

“…However, there are HLA-G free H chains (FHCs), which are probably formed by dissociation of ␤ 2 m from the conformed HLA-G protein (24,25). We and others have demonstrated previously that the HLA-G1 protein is expressed on the cell surface in a unique pattern of disulfidelinked oligomers (26 -28).…”

mentioning

confidence: 99%

The CD85J/Leukocyte Inhibitory Receptor-1 Distinguishes between Conformed and β2-Microglobulin-Free HLA-G Molecules

Gonen‐Gross¹,

Achdout²,

Arnon³

et al. 2005

108

124

For a proper development of the placenta, maternal NK cells should not attack the fetal extravillous cytotrophoblast cells. This inhibition of maternal NK cells is partially mediated via the nonclassical MHC class I molecule HLA-G. Recently, we demonstrated that HLA-G forms disulfide-linked high molecular complexes on the surface of transfected cells. In the present study, we demonstrate that HLA-G must associate with β2m for its interaction with CD85J/leukocyte Ig-like receptor-1 (LIR-1). Although HLA-G free H chain complexes are expressed on the surface, they are not recognized and possibly interfere with CD85J/LIR-1 and HLA-G interaction. The formation of these complexes on the cell surface might represent a novel mechanism developed specifically by the HLA-G protein aimed to control the efficiency of the CD85J/LIR-1-mediated inhibition. We also show that endogenous HLA-G complexes are expressed on the cell surface. These findings provide novel insights into the delicate interaction between extravillous cytotrophoblast cells and NK cells in the decidua.

“…Mild acid treatment was performed by resuspending the cells in 0.2 ml of 0.2 M citrate-phosphate buffer (pH 3.0) supplemented with 0.1% BSA (29). After a 1-min incubation on ice the sample was neutralized by adding an excess of cold 0.1% BSA in PBS (pH 7.2), centrifuged, and rinsed with PBS (pH 7.2).…”

Section: Mild Acid Treatmentmentioning

confidence: 99%

“…No staining was revealed after LPS and LPS plus ATP treatment. Positive staining with MEM-G1 was obtained treating LPS-activated monocytes with mild acid that dissociates ␤ 2 -microglobulin from HLA-G H chain (29). Fig.…”

Section: Atp Inhibits Membrane Expression Of Hla-g Moleculesmentioning

confidence: 99%

Extracellular ATP Acting at the P2X7 Receptor Inhibits Secretion of Soluble HLA-G from Human Monocytes

Rizzo¹,

Ferrari

Melchiorri³

et al. 2009

Bacterial LPS induces the release of ATP from immune cells. Accruing evidence suggests that extracellular ATP participates in the inflammatory response as a proinflammatory mediator by activating the inflammasome complex, inducing secretion of cytokines (IL-1, IL-18) and cell damaging agents such as oxygen radicals, cationic proteins, and metalloproteases. It is not known whether ATP can also act as a proinflammatory mediator by inhibiting production of molecules down-modulating the immune response. Here, we show that extracellular ATP impairs in an IL-10-dependent fashion the expression of the tolerogenic soluble and membrane-bound HLA-G Ag in human monocytes. The effect of ATP was mimicked by BzATP (3′-O-(4-benzoyl)benzoyl-ATP) and greatly reduced by pretreatment with oATP (periodate-oxidized ATP), KN-62 (1-[N,O-bis(5-isoquinoline-sulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine), and an anti-P2X7 mAb, thus pointing to a specific role of the P2X7 receptor. The effect of ATP was time- and dose-dependent and was not due to a decrease in expression of IL-10 receptor. Inhibition by ATP was reverted by supplementation of culture medium with exogenous IL-10. Due to the well-known immunosuppressive activity of IL-10 and soluble HLA-G, this novel effect of ATP might be relevant for the pathophysiology and therapy of inflammatory disorders.