Immune Conversion of Tumor Microenvironment by Oncolytic Viruses: The Protoparvovirus H-1PV Case Study

Abstract

Cancer cells utilize multiple mechanisms to evade and suppress anticancer immune responses creating a "cold" immunosuppressive tumor microenvironment. Oncolytic virotherapy is emerging as a promising approach to revert tumor immunosuppression and enhance the efficacy of other forms of immunotherapy. Growing evidence indicates that oncolytic viruses (OVs) act in a multimodal fashion, inducing immunogenic cell death and thereby eliciting robust anticancer immune responses. In this review, we summarize information about OV-mediated immune conversion of the tumor microenvironment. As a case study we focus on the rodent protoparvovirus H-1PV and its dual role as an oncolytic and immune modulatory agent. Potential strategies to improve H-1PV anticancer efficacy are also discussed.

Keywords: H-1PV; checkpoint blockade; combination therapy; immunogenic cell death; immunotherapy; oncolytic viruses; tumor microenvironment.

Figure 1

Induction of immune conversion of tumor microenvironment by OVs. The left panel depicts a cold tumor microenvironment (TME). In addition to tumor cells, some other components of the TME are shown, i.e., blood vessel with endothelial cells, CAFs, ECM, and few infiltrating immune cells. These immune cells (mainly Treg, MDSC, and TAM having a M2 immunosuppressive status), together with other cells of TME (e.g., CAF and tumor cells themselves), produce and secrete chemo/cytokines, growth factors, and other molecules which contribute to create an immunosuppressive TME. This “cold” TME supports tumor development and metastasis, and confers resistance to (immuno) therapies. The right panel depicts an inflamed TME after intravenous OV treatment. OVs reach the tumor through the blood stream and act in a multimodal fashion to eliminate cancer cells. OVs specifically replicate in and kill cancer cells by inducing immunogenic cell death. Virus-induced cancer cell lysis is associated with the release of progeny virus particles, TAAs, DAMPs, PAMPs, and pro-inflammatory/immunostimulatory cytokines which contribute to recruiting immune cells in the TME and inducing maturation of DCs, thereby triggering innate as well as adaptive immune responses (inset a). DCs migrate to the draining lymph nodes where they cross-present TAAs to T cells (inset b). After expansion, T cells infiltrate the TME and participate in the destruction of cancer cells together with other effector cells such as NK cells and M1-converted macrophages (inset c). Some OVs may also infect endothelial cells and induce disruption of tumor vasculature, potentially facilitating immune cell migration into the TME (inset d).