NKG2D-Deficient Mice Are Defective in Tumor Surveillance in Models of Spontaneous Malignancy

Abstract

Ligands for the NKG2D stimulatory receptor are frequently upregulated on tumor lines, rendering them sensitive to natural killer (NK) cells, but the role of NKG2D in tumor surveillance has not been addressed in spontaneous cancer models. Here, we provided the first characterization of NKG2D-deficient mice, including evidence that NKG2D was not necessary for NK cell development but was critical for immunosurveillance of epithelial and lymphoid malignancies in two transgenic models of de novo tumorigenesis. In both models, we detected NKG2D ligands on the tumor cell surface ex vivo, providing needed evidence for ligand expression by primary tumors. In a prostate cancer model, aggressive tumors arising in NKG2D-deficient mice expressed higher amounts of NKG2D ligands than did similar tumors in wild-type mice, suggesting an NKG2D-dependent immunoediting of tumors in this model. These findings provide important genetic evidence for surveillance of primary tumors by an NK receptor.

NKG2D ligand expression in pediatric brain tumors

“…This is especially noteworthy when taken with the expectation that nearly 100% of circulating NK cells express NKG2D 63 , and the loss of NKG2D receptor expression in mouse models of cancer predisposes those animals to a variety of spontaneously arising tumors. 64 These findings for pediatric WHO grade I tissue are in contrast to what we observe in adult glioblastoma WHO grade IV tissue (Fig. 5).…”

Pharmacological activation of p53 triggers anticancer innate immune response through induction of ULBP2

“…2,14 Mice with NKG2D deficiency had enhanced spontaneous tumorigenesis and higher amount of NKG2D ligands expressed on tumor cells, suggesting a crucial role of NKG2D system in immunosurveillance against tumorigenesis. 15 The importance of the NKG2D system in tumor immunosurveillance was also verified by comparing four engineered mouse strains with different deficiencies in their immunocompetence-the mice with deficiency of NKG2D ligands had increased tumorgenesis. 16 NKG2D ligands expressed in humans, including MICA, MICB and ULBP1 through 6,16 are induced by the signaling pathways implicated in tumorigenesis.…”

“…16 Both in vitro and in vivo studies in mice and humans show that upregulation of NKG2D ligand expression on tumor cell surface successfully activates anti-tumor immune responses, 19 while the expression of these ligands is frequently lost during tumor progression due to selective pressure by the immune system. 15,20,21 Thus to develop effective approaches for cancer immunotherapy based on NKG2D system, strategies for enhancing NKG2D ligand expression in tumors are urgently required. However, current understanding of the regulation of NKG2D ligand expression is limited.…”

Tumor-associated and immunochemotherapy-dependent long-term alterations of the peripheral blood NK cell compartment in DLBCL patients

“…[23][24][25][26] Among these, killer cell lectin-like receptor K1 (KLRK1, better known as NKG2D) plays an important role in the immunosurveillance against human and mouse model lymphoma, by recognizing stress-induced ligands belonging to the MIC (MICA and MICB) and ULBP (ULBP1-6) families. [29][30][31][32][33][34][35] Expression and/or functional capability of activating receptors is orderly acquired during NK cell differentiation [20][21][22] and can be modulated upon activation and/or ligand engagement. [29][30][31][32][33][34][35][36][37] Activated NK cells also rapidly secrete a variety of cytokines and chemokines, such as interferon g (IFNg), that amplify the recruitment and activation of other participants to the antitumor response.…”