Immunohistochemical Validation and Expression Profiling of NKG2D Ligands in a Wide Spectrum of Human Epithelial Neoplasms

Abstract

The MHC class I-chain-related proteins (MICs) and the UL16-binding proteins (ULBPs) are inducible stress response molecules that work as activators of a specific receptor, NKG2D, which is expressed on effector cells, such as NK cells and subsets of T cells. In this study, we sought to explore the biological significance of NKG2D ligands in human neoplasms by comprehensively examining the immunohistochemical expression profile of NKG2D ligands in a variety of human epithelial neoplasms. Following careful validation of the immunohistochemical specificity and availability of anti-human ULBP antibodies for formalin-fixed paraffin-embedded (FFPE) materials, the expression of NKG2D ligands was analyzed in FFPE tissue microarrays comprising 22 types of epithelial neoplastic tissue with their non-neoplastic counterpart from various organs. Hierarchical cluster analysis demonstrated a positive relationship among ULBP2/6, ULBP3, ULBP1, and ULBP5, whose expression patterns were similar across all of the neoplastic tissues examined. In contrast, MICA/B, as well as ULBP4, did not appear to be related to any other ligand. These expression profiles of NKG2D ligands in human neoplasms based on well-validated specific antibodies, followed by hierarchical cluster analysis, should help to clarify some functional aspects of these molecules in cancer biology, and also provide a path to the development of novel tumor-type-specific treatment strategies.

Immune evasion in renal cell carcinoma: biology, clinical translation, future directions

“…The interaction of NKG2D with multiple ligands leads to the activation of NK cells and co-stimulation of CD8 T cells 60 . RCC has been shown to have a marked under-expression of NKG2D ligands 61 , thereby inhibiting this signal.…”

Immune evasion by TGFβ-induced miR-183 repression of MICA/B expression in human lung tumor cells

“…In fact, MICA/B has been reported on numerous human cancer types, including lung cancer, and its level of expression can be prognostic. [32][33][34] Thus, a potent means for transformed tumor cells to escape immune detection is to downregulate the surface expression of NKG2D ligands. Despite the ability of NK cells to penetrate the tumor bed, the absence of NKG2D ligands could blind the NK effector cells to the surrounding tumor cells.…”

Stress Signal ULBP4, an NKG2D Ligand, Is Upregulated in Multiple Sclerosis and Shapes CD8 + T-Cell Behaviors

“…Indeed, targeting ULBP4, without altering other ligands that might contribute to important immune functions, could yield a very specific therapy. Importantly, it is known that ULBP4 is implicated in various types of cancers 42 - 44 ; however, current data suggest that ULBP4 is not expressed in CNS-related cancers in adults. Although MICA, MICB, and ULBP1-2 are detected at the protein level in human adult glioblastoma multiforme (GBM) and meningioma samples, ULBP3 and ULBP4 are not.…”