Soluble NKG2D ligands in the ovarian cancer microenvironment are associated with an adverse clinical outcome and decreased memory effector T cells independent of NKG2D downregulation

The immune receptor NKG2D is predominantly expressed on NK cells and T cell subsets and confers anti-tumor activity. According to the current paradigm, immune surveillance is counteracted by soluble ligands shed into the microenvironment, which down-regulate NKG2D receptor expression. Here, we analyzed the clinical significance of the soluble NKG2D ligands sMICA and sULBP2 in the malignancy-associated ascites of ovarian cancer. We show that high levels of sMICA and sULBP2 in ascites were associated with a poor prognosis. Ascites inhibited the activation of normal NK cells, which, in contrast to the prevailing notion, was not associated with decreased NKG2D expression. Of note, an inverse correlation of soluble NKG2D ligands with effector memory T cells and a direct correlation with pro-tumorigenic CD163(+)CD206(+) macrophages was observed. Thus, the role of soluble NKG2D ligands within the ovarian cancer microenvironment is more complex than anticipated and does not exclusively function via NKG2D downregulation.