Embelin Promotes Oncolytic Vaccinia Virus-Mediated Antitumor Immunity Through Disruption of IL-6/STAT3 Signaling in Lymphoma

Abstract

Objective: Oncolytic virotherapy is a promising alternative to conventional treatment, yet limited viral replication and immune-negative feedback are the major hurdles to effective viro-immunotherapy. Methods: In this study, we found that use of an adjuvant of embelin, a small molecular inhibitor of XIAP, increased the replication of oncolytic vaccinia virus (OVV) by mitigating antiviral innate immunity. Moreover, embelin suppresses constitutive STAT3 phosphorylation and mitigates OVV-induced activation of STAT3 in lymphoma. In the subcutaneous lymphoma model, embelin significantly enhanced the therapeutic efficacy of OVV and prolonged the survival. In addition, embelin significantly increased the OVV-induced infiltration of T cells and NK cells and decreased the number of OVV-induced myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Results: Our results explored the ability of OVV and embelin in combination to enhance lymphoma cell lysis, revealing a beneficial combinatorial effect wherein both lymphoma cell lysis and OVV replication were enhanced both in vitro and in an in vivo murine model system. Conclusion: Our findings indicate the utility of embelin as an adjuvant for oncolytic viro-immunotherapy.