Abstract
MICA is a major ligand for the NKG2D immune receptor, which plays a key role in activating natural killer (NK) cells and cytotoxic T cells. We analyzed NKG2D ligand expression on a range of cell types and could demonstrate that MICA expression levels were closely linked to cellular growth mode. While the expression of other NKG2D ligands was largely independent of cell growth mode, MICA expression was mainly found on cells cultured as adherent cells. In addition, MICA surface expression was reduced through increase in cell–cell contact or loss of cell–matrix adherence. Furthermore, we found that the reduction in MICA expression was modulated by focal adhesion kinase (FAK)/Src signaling and associated with increased susceptibility to NK cell-mediated killing. While the mechanisms of tumor immune evasion are not fully understood, the reduction of MICA expression following loss of attachment poises a potential way by which metastasizing tumor cells avoid immune detection. The role of FAK/Src in this process indicates a potential therapeutic approach to modulate MICA expression and immune recognition of tumor cells during metastasis.
Highlights
Tumors are complex networks of cells that can interact with the extracellular matrix and neighboring normal tissues [1]
This study demonstrates that MICA, a key activating ligand for NKG2D, is mainly expressed on adherent cells and that this expression is reduced upon loss of surface attachment and increased cell–cell contact, underscoring the importance of the focal adhesion kinase (FAK)/sarcoma oncogene family (Src) signaling pathway in modulating MICA expression
MICA surface expression was absent or low in most of the suspension cell lines tested (Figure 1B; Figure S1B in Supplementary Material). This was not the case for other NKG2D ligands as UL16 binding proteins (ULBPs) were often found in suspension cell lines, while MICB was not always expressed in adherent cells (Figure 1C)
Summary
Tumors are complex networks of cells that can interact with the extracellular matrix and neighboring normal tissues [1]. As adherent cancer-derived cell lines lose contact with their underlying surface, they tend to aggregate into three-dimensional tumor-like masses that recapitulate some features of in vivo tumor growth [3]. These “spheroids” reflect aspects of solid tumors in morphology, compact organization, growth dynamics, capacity to Regulation of MICA by Cell Contact and Adhesion develop a necrotic core, proliferation in the periphery, induction of hypoxia, and increased resistance to chemo- and radiotherapy [4, 5]. Cell–cell and cell–matrix adhesion receptors participate in intracellular communication linked to the cytoskeleton, affecting cell shape and polarity, cytoplasmic organization, cell motility, intracellular signal transduction, cancer progression, and metastasis [6]
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