Lighting a Fire in the Tumor Microenvironment Using Oncolytic Immunotherapy

Abstract

Oncolytic virus (OV) therapy is potentially a game-changing cancer treatment that has garnered significant interest due to its versatility and multi-modal approaches towards tumor eradication. In the field of cancer immunotherapy, the immunological phenotype of the tumor microenvironment (TME) is an important determinant of disease prognosis and therapeutic success. There is accumulating data that OVs are capable of dramatically altering the TME immune landscape, leading to improved antitumor activity alone or in combination with assorted immune modulators. Herein, we review how OVs disrupt the immunosuppressive TME and can be used strategically to create a "pro-immune" microenvironment that enables and promotes potent, long-lasting host antitumor immune responses.

Keywords: Cancer immunotherapies; Combination therapies; Oncolytic viruses; Tumor microenvironment.

Fig. 1

Oncolytic viruses in the tumor microenvironment. In addition to their cancer cell lysing activity, OVs can target several other components of the TME including CAFs and ECs. Moreover, OV infection causes the release of inflammatory cytokines, DAMPs, PAMPs and TAAs in the tumor milieu. This results in the recruitment and maturation of innate immune cells which can cross-present TAAs to CD8⁺ T cells, thus generating populations of TAA-specific CTLs. The generation of an antitumor immune response mediated by OV infection also counteracts the immune suppression associated to Tregs and MDSCs. Thus, OV infection engages both the innate and adaptive arms of the immune system which act together to destroy the tumor mass and generate potent antitumor immune responses. These properties of OV-infected tumors can be harnessed to rationally combine therapies that enhance OV replication and the immune response they generate.

Fig. 2

Warming up immunologically “cold” tumors with OVs. PanCO2 tumor-bearing mice treated with an infected cell vaccine (ICV) (right) show higher intratumoral CD3⁺ cells in the TME in comparison to its untreated counterpart (left) (large mass of staining is a peritoneal lymph node). ICV technology harnesses the immune activation properties of both OVs and tumor cell vaccines to maximize therapeutic benefit. Following treatment, the infiltration of activated T cells in the local TME allows previously immunologically ignorant or immunosuppressed tumors to enact a potent antitumor immune response towards tumor destruction. Scale bar: 300 μm.

Fig. 3

Oncolytic virus invasion of the tumor serves as in situ vaccination. After colonization of the tumor, OVs mediate direct lysis of cancer cells as well as components of the TME (e.g. CAFs and ECs). The release of danger signals and pro-inflammatory cytokines in the TME by cancer cells undergoing ICD after OV infection, as well as the OV itself, attract and activate immune cells. Among them, DCs will engulf OV-infected tumor cells and migrate to the lymph node, where the antigen cross-presentation to specific CTLs will take place. The TAA-specific CTLs then enter the blood stream to reach the tumor, where they can exert their cytotoxic activity against cancer cells displaying specific TAAs. OV therapy thus induces in situ vaccination leading to specific antitumor immune responses that act in concert with the virus to eradicate the tumor.