1. State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
2. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
3. National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, College of Bioengineering, Hubei University of Technology, Wuhan 430068, China.
4. Department of Immunology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
# These authors have contributed equally to this work.
Rationale: Oncolytic virus (OV) therapy as a cancer therapy that improves immune status makes it a favorable candidate for optimizing immunotherapy strategies. Existing studies have focused on characterizing the disturbance of the tumor microenvironment (TME) by OV therapy. However, the changes in systemic immunity induced by OV were largely ignored, which would prevent the further understanding and optimization of oncolytic viruses.
Methods: The HSV-2-based oncolytic virus OH2 was used to treat tumor-bearing mouse models. The peripheral blood samples were then collected for single-cell RNA sequencing (scRNA-seq). The scRNA-seq data were analyzed using Cell Ranger, Seurat, and other bioinformatics tools. Key findings were further validated by ELISA, immunohistochemistry, flow cytometry, in vivo experiments, and clinical samples.
Results: Our data showed that OH2 therapy effectively activated systemic immunity and induced a sustained anti-tumor immune response. One major impact of OH2 on systemic immunity was to boost Ccl5 production, which correlated with clinical response. Besides, the cytotoxic ability of peripheral cytotoxic Cd8+ T cells and mature NK cells was elevated by OH2. Further analysis revealed that the interaction of monocytes with T cells and NK cells was critical for systemic immune remodeling and activation. We also found that systemic immune responses induced by OH2 could effectively reshape the microenvironment of distant tumor lesions and inhibit their progression.
Conclusions: This study is the first to comprehensively characterize the effects of OV therapy on systemic immunity, which not only sheds new light on the anti-tumor mechanisms of OH2, but also contributes to the establishment of companion diagnostics for OH2 treatment and the improvement of oncolytic therapy strategies.
Keywords: Oncolytic virus, Single cell sequencing, Systemic immunity, Ccl5