Viral antigen mediated NKp46 activation of NK cells results in tumor rejection via NK-DC crosstalk

Abstract

Natural killer (NK) cells play a critical role in antitumor immunity, their activation being regulated through NK cell receptors. Although the endogenous ligands for these receptors are largely unknown, viral ligands have been identified. We investigated the ability of an activating NK receptor ligand derived from the mumps virus, haemagglutinin-neuraminidase (HN) to enhance NK activation against tumor cells. HN-expressing B16.OVA tumor cells induced stronger activation of NK cells compared with B16.OVA cells and also promoted dendritic cell (DC) activation toward a DC1 phenotype, in vitro. Moreover, incubation of DCs, NK cells and HN-expressing B16-OVA cells further enhanced NK cell activation through the NK-DC crosstalk, in a cell-to-cell contact- and IL-12-dependent fashion. Immunization of mice with HN-expressing B16-OVA cells resulted in > 85% survival rate after subsequent challenge with parental B16 or B16.OVA tumor cells. Tumor rejection was dependent on both NK and CD8+ T cells but not on CD4+ T cells, demonstrating induction of an effective adaptive immune response through innate immune cell activation. Our data indicate the potential of using robust NK cell activation, which through the NK-DC crosstalk stimulates effective antitumor responses, providing an alternate vaccine strategy.

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

“…[22][23][24][25]58 The immunosuppressive cytokine TGF-b and the cells that are its main source, Treg cells, have been reported to downregulate surface expression of NKG2D and other activating NK cell receptors in the tumor microenvironment, thereby impairing NK cell function and further promoting tumor progression. 46,68 PGE2 and IDO derived from tumor cells can also downregulate NKG2D expression.…”

“…[26][27][28][29][30][31] With disease progression, decreased expression of NKG2D can be correlated with decreased NK cell function, most notably reduced cytotoxicity. The significantly 22,28,[34][35][36] Moreover, these alterations are not limited to activating receptors on NK cells. There are several studies that show that NK cell dysfunction is correlated with increased expression of the inhibitory receptor NKG2A and HLA-E. 26,37 Another study provided evidence of a significantly increased level of KIR3DL1-positive NK cells in patients with PC, GC and CRC.…”

“…Consistent with the view that NKRs are important components of anti-tumor immune responses, several mechanisms that tumors use to evade NKR-induced NK cell-mediated killing of tumor cells have been identified. [18][19][20][21][22][23] Despite these associations, the mechanisms linking NKRs and HCC are not completely understood. In this review, we focus on the role of these NK cell receptors in anti-tumor immune responses.…”

Chronic alcohol drinking: Liver and pancreatic cancer?

“…Upregulation of inhibitory receptors and downregulation of activating receptors on NK cells makes cancer cells ''invisible'' to immune surveillance. Numerous studies have found a reduction in the proportion of NK cells in peripheral blood of HCC patients [37], and a decrease in the expression of NK cell activating receptors during the development and progression of HCC [38].…”

Targeting glioblastoma with oncolytic adenovirus delta 24

“…[26] ANTITUMOR IMMUNE RESPONSE Another important aspect of oncolytic virotherapy is the induction of augmented antitumor immune response. [27,28] Ad-Δ24-RGD has been shown to induce antiglioma immunity and to enhance the presentation of tumor-associated antigens to immune cells. [29] These findings provide the base for further genetic manipulation of Ad-Δ24 in order to drive the production of immunostimulatory factors (like granulocyte-macrophage colony stimulating factor) that can possibly mediate more robust therapeutic effects.…”