The role of NK cells in oncolytic viral therapy: a focus on hepatocellular carcinoma

Abstract

Natural killer (NK) cells have a key role in host anti-tumour immune responses via direct killing of tumour cells and promotion of adaptive immune responses. They are therefore attractive targets to promote the anti-tumour efficacy of oncolytic viral therapies. However, NK cells are also potent components of the host anti-viral immune response, and therefore have the potential for detrimental anti-viral responses, limiting the spread and persistence of oncolytic viruses. Oncolytic viruses are currently being investigated for the treatment of hepatocellular carcinoma (HCC), a leading cause of cancer-related death with a high unmet clinical need. In this review, we highlight the role of NK cells in oncolytic virus therapy, their potential for improving treatment options for patients with HCC, and discuss current and potential strategies targeting NK cells in combination with oncolytic viral therapies.

The application of autologous cancer immunotherapies in the age of memory-NK cells

“…Notably, these 2 cell types are the most widely used lymphocytes in cancer immunotherapy, which aims to target cancer cell populations through opposites mechanisms, suggesting the existence of cytotoxic synergies ( 37 , 101 ). Additionally, IFN-γ production of NK cells in the TME upregulates MHC-I expression by tumor cells, increasing activatory targets for cytotoxic T cells ( 106 , 107 ). Therefore, combining NK cells with T cells is a potential mechanism to achieve tumor regression.…”

“…For instance, intra-tumoral transcripts CCL5, XCL1, and XCL2 closely correlate with NK cells and cDC1 gene signatures that were also associated with patient survival ( 111 ). This cell interaction suggested an excellent tool for the success of cell immunotherapy since NK cells are required to promote the optimal cytotoxicity response of T cells through the recruitment of dendritic cells in the tumor site ( 21 , 107 , 111 , 112 ).…”

“…Other combinatorial studies have also demonstrated additional avenues for potentiating the anti-cancer effect of NK-based therapies. For instance, it was reported that the combined treatment of NK cells with oncolytic viruses (OV, therapeutically beneficial viruses that have the ability to replicate and kill cancer cells) enhanced the cytotoxicity of OV and induced NK cell infiltration ( 107 , 126 – 128 ). Another study found that using a checkpoint antibody blocking TIGIT, an inhibitory cell surface receptor, reversed the NK cell exhaustion and enhanced NK cell cytotoxicity, inhibiting in vivo colon, breast, and melanoma tumor growth ( 129 ).…”

Immunotherapies inducing immunogenic cell death in cancer: insight of the innate immune system

“…The anti-viral immunity triggered against viral antigens from the resultant infection is also a key player during OVbased therapies, as tumour cell infection promotes the antiviral immune response, which can be seen as a negative response triggered against OVs, but it helps to settle an inflammatory site that turns "cold" tumours "warm" (74). However if unbalanced, this immune response could induce premature clearance of OVs and compromise their antitumour efficacy (75), as it has been observed in herpes simplex virus (oHSV) therapy, where activated NK cells reduce the anti-tumour efficacy of HSV in glioblastoma cells (76). In this regard, the combination of transforming growth factor beta (TGFb) and oHSV therapy inhibits NK cell recruitment and function, resulting in enhanced viral replication in glioblastoma mouse models (77).…”