NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors

Abstract

The role of the immune response to oncolytic Herpes Simplex viral (oHSV) therapy for glioblastoma is controversial. Within hours of oHSV infection of human or syngeneic glioblastoma in mice, activated natural killer (NK) cells are recruited to the site of infection. This response significantly diminished the efficacy of glioblastoma virotherapy. oHSV-activated NK cells coordinated macrophage and microglia activation within tumors. In vitro, human NK cells preferentially lysed oHSV-infected human glioblastoma cell lines. This enhanced killing depended on NK cell natural cytotoxicity receptors (NCR) NKp30 and NKp46, whose ligands were up-regulated in oHSV-infected glioblastoma cells. HSV titers and oHSV efficacy were increased in Ncr1−/− mice and in a Ncr1−/− NK cell adoptive transfer model of glioma, respectively. These in vitro and in vivo (mouse) results demonstrate that glioblastoma virotherapy is partly limited by an antiviral NK cell response involving specific NCRs, uncovering novel potential targets to enhance cancer virotherapy.

Modulation of CD112 by the alphaherpesvirus gD protein suppresses DNAM-1–dependent NK cell-mediated lysis of infected cells

“…At the same time, our findings may have consequences for the design of herpes-based therapeutic vectors. Specifically, the use of attenuated HSV-1-based oncolytic vectors for glioblastoma therapy is limited by premature clearance of the viral vector by NK cells of the recipient (18). We observed that expression of PRV gD or HSV-2 gD in the U87-MG glioblastoma cell line reduces cell surface CD112 and DNAM-1 binding (Fig.…”

“…Indeed, a limiting factor in HSV vector-based oncotherapy is the premature clearance of the viral vector by NK cells (18).…”

“…The sum of these signals determines the outcome of NK cell effector responses including cytotoxicity against NK-sensitive targets (20). A variety of NK activating receptors are involved in recognition of virus-infected cells (18,(21)(22)(23)(24)(25)(26). One of the important NK activating receptors is DNAX accessory molecule 1 (DNAM-1), which binds to CD112 (nectin-2) and CD155 (poliovirus receptor, PVR), whose expression can be induced in both virus infected and tumor cells (5,(26)(27)(28).…”

Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

“…27 This upregulation resulted in the killing of infected glioblastoma cells through NKp46-expressing NK cells. NKp46 has also been implicated in controlling tumor metastasis in animals with B16 melanoma or Lewis lung carcinoma D122.…”

The therapeutic efficacy of the oncolytic virus Delta24-RGD in a murine glioma model depends primarily on antitumor immunity

“…5 However, little is known about the role of the immune system in oncolytic adenovirus therapy, especially in the context of brain tumors. On one hand, the antiviral immune response could hamper oncolytic efficacy, 6 whereas on the other hand, a beneficial antitumor immune response could be elicited, as has been reported for other oncolytic virus therapies. 7 We hypothesized that intratumoral replication of Delta24-RGD would drive a pro-inflammatory immune response remodeling the glioma-induced immunosuppressive tumor microenvironment to one that fosters antitumor immunity.…”