Gastric cancer progression may involve a shift in HLA‐E profile from an intact heterodimer to β2‐microglobulin‐free monomer

Phenotypic expression of human leukocyte antigen (HLA)‐E on the surface of tumor lesions includes intact heterodimer [HLA‐E heavy chain and β2‐microglobulin (β2m)] and β2m‐free monomer. Anti‐HLA‐E monoclonal antibodies (mAbs), MEM‐E/02 or 3D12 bind to the peptide sequences in β2m‐free HLA‐E, which is common and shared with HLA‐Ia monomers. A newly developed monospecific anti‐HLA‐E mAb (TFL‐033) recognizes HLA‐E‐restricted peptide sequences on α1 and α2 helices away from β2‐m‐site. Tumor progression may involve shedding of β2‐m from HLA‐E or overexpression of β2m‐free monomers. There is a need to identify and distinguish the different phenotypic expression of HLA‐E, particularly the intact heterodimer from the β2m‐free monomer on the surface of tumor lesions. Because of the unique peptide‐binding affinities of the mAbs, it is hypothesized that TFL‐033 and MEM‐E/02 may distinguish the phenotypic expressions of cell surface HLA‐E during stages of tumor progression. Only TFL‐033 stained diffusely the cytoplasm of normal mucosa. The incidence and intensity of TFL‐033 staining of the cell surface in early stages, poorly or undifferentiated and non‐nodal lesions and in diffuse carcinoma is greater than that of MEM‐E/02. Whereas MEM‐E/02 stained terminal stages, adenocarcinoma and lymph node metastatic lesions intensely, either owing to increased expression of β2m‐free HLA‐E with tumor progression or owing to expression of HLA‐Ia molecules. Our study evaluates the relative diagnostic potential of HLA‐E‐monospecific TFL‐033 and the HLA‐Ia‐reactive MEM‐E/02 for determining the specific distribution and immunodiagnosis of different phenotypic expression HLA‐E in tumor lesions, and the structural and functional alterations undergone by HLA‐E during tumor progression. What's new? Structural and functional alterations of human leukocyte antigens (HLA) are implicated in tumor immune escape. Identifying distinct forms of HLA‐E on tumor cells could help shed light on alterations undergone by HLA‐E during tumor progression and functional implications. This study assessed the relative diagnostic potential of HLA‐E‐monospecific TFL‐033 and HLA‐Ia‐reactive MEM‐E/02 mAbs. Only TFL‐033 was able to stain diffusely normal mucosa cytoplasm. The incidence of TFL‐033 staining of cell surface was greater than that of MEM‐E/02 in early‐stages, poorly or undifferentiated, and non‐nodal lesions, and in diffuse carcinoma. The incidence of MEM‐E/02 staining was higher for adenocarcinoma an