Abstract
Oncolytic virotherapy can lead to systemic antitumor immunity, but the therapeutic potential of oncolytic viruses in humans is limited due to their insufficient ability to overcome the immunosuppressive tumor microenvironment (TME). Here, we showed that locoregional oncolytic virotherapy upregulated the expression of PD-L1 in the TME, which was mediated by virus-induced type I and type II IFNs. To explore PD-1/PD-L1 signaling as a direct target in tumor tissue, we developed a novel immunotherapeutic herpes simplex virus (HSV), OVH-aMPD-1, that expressed a single-chain variable fragment (scFv) against PD-1 (aMPD-1 scFv). The virus was designed to locally deliver aMPD-1 scFv in the TME to achieve enhanced antitumor effects. This virus effectively modified the TME by releasing damage-associated molecular patterns, promoting antigen cross-presentation by dendritic cells, and enhancing the infiltration of activated T cells; these alterations resulted in antitumor T-cell activity that led to reduced tumor burdens in a liver cancer model. Compared with OVH, OVH-aMPD-1 promoted the infiltration of myeloid-derived suppressor cells (MDSC), resulting in significantly higher percentages of CD155+ granulocytic-MDSCs (G-MDSC) and monocytic-MDSCs (M-MDSC) in tumors. In combination with TIGIT blockade, this virus enhanced tumor-specific immune responses in mice with implanted subcutaneous tumors or invasive tumors. These findings highlighted that intratumoral immunomodulation with an OV expressing aMPD-1 scFv could be an effective stand-alone strategy to treat cancers or drive maximal efficacy of a combination therapy with other immune checkpoint inhibitors.
Highlights
Cancer immunotherapy has achieved great therapeutic success over the past several years
These findings provided rationale for targeting the PD-1/ PD-L1 axis directly in tumors, which was further supported by studies demonstrating that PD-L1 blockade can potentiate the efficacy of oncolytic virotherapy [7, 8]
The results revealed that the phagocytosis of cancer cells by dendritic cells (DC) was significantly increased when cancer cells were preinfected with virus, and OVH-aMPD-1 induced much stronger phagocytosis than OVH (Fig. 3I and J; Supplementary Fig. S11A)
Summary
Cancer immunotherapy has achieved great therapeutic success over the past several years. The tumor microenvironment (TME) in many tumor types that do not respond to immunotherapy lacks infiltration of tumor-specific immune cells, lacks neoantigen expression and costimulatory signaling, and exhibits coinhibitory signaling, which restricts the efficacy of cancer therapy [2]. Reversing the immunosuppressive TME is the most important challenge in the development of immunotherapeutics [3]. Oncolytic viruses (OV) can selectively replicate in tumor cells and provoke a virus-specific or tumor-specific inflammatory response in the TME [4]. Oncolytic virotherapy is a promising therapeutic strategy for cancer, but further preclinical studies are needed to maximize its therapeutic efficacy [6]. The antitumor efficacy of oncolytic virotherapy is significantly enhanced antitumor when combined with systemic immune check-
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