Table 3.

Interactions between tumor, the host immune system, and oncolytic viruses attenuating anti-cancer effects, or increasing toxicity.

Immune Effect	Innate mechanism	Adaptive mechanism
Decreased anti-tumor immunity	↓Tumor cell Immunogenicity, due to ↓caspase expression [P]*97 ↓ Antitumor NK cell activity, due to sustained NKG2D ligand expression [P]98	Tumor resistance to immune killing, via ↓death receptors [P]94 Suppression of ATI, due to increased immune-suppressive Treg numbers [C]68 [P]95
OV stimulated anti-viral immunity	OV inactivation with potential reduced oncolysis due to: Interferon response (VSV) [P]80 Complement mediated killing (HSV) [P]99	OV inactivation with potential reduced oncolysis due to: Induction of nAb response (VV, HSV, reovirus, VSV) [C]21,22,25 [P]50–52 Potent anti-viral, versus TS-CTL, immune response (reovirus, VSV) [P]48–49
Manipulation of anti-viral immunity	Decreased tumor killing following loss of bystander effect, due to attenuation of innate response (VSV) [P]61	Increased in vivo toxicity from OV, due to ablation of nAb response (reovirus) [P]100

The complex interplay between tumor, host immunity and OV may be detrimental to anti-tumor therapy. Direct loss of immune control of tumors may be observed, oncolytic therapy may be attenuated by the host immune response to OVs, and OV toxicity may be increased. Understanding and avoiding these interactions may serve to enhance OV mediated therapy.

Abbreviations: [C], clinical evidence; [P], preclinical evidence; NKG2D, activating receptors for NK cells; Tregs, T regulatory cells.

^*References in superscript.