Cooperation of Oncolytic Herpes Virotherapy and PD-1 Blockade in Murine Rhabdomyosarcoma Models

• Published in: Scientific reports Vol. 7; no. 1; pp. 2396 - 10
• Main Authors: Chen, Chun-Yu, Wang, Pin-Yi, Hutzen, Brian, Sprague, Les, Swain, Hayley M., Love, Julia K., Stanek, Joseph R., Boon, Louis, Conner, Joe, Cripe, Timothy P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.05.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/31; 38; 38/77; 38/90; 631/67/1059/2325; 631/67/1798; 631/67/2332; 64/60; Animal models; Animals; Antibodies, Monoclonal - pharmacology; Antitumor activity; Apoptosis; CD25 antigen; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell death; Children; Combined Modality Therapy - methods; Cytokines; Cytokines - genetics; Cytokines - immunology; Cytotoxicity; Dendritic Cells - drug effects; Dendritic Cells - immunology; Female; Foxp3 protein; Gene Expression; Herpes simplex; Humanities and Social Sciences; Immunosuppression; Immunotherapy; Injections, Intralesional; Injections, Intraperitoneal; Ligands; Lymphocytes; Lymphocytes T; Lysis; Major histocompatibility complex; Mice; Mice, Inbred C57BL; multidisciplinary; Neoplasms, Experimental; Oncolysis; Oncolytic Virotherapy - methods; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Rhabdomyosarcoma; Rhabdomyosarcoma - genetics; Rhabdomyosarcoma - immunology; Rhabdomyosarcoma - mortality; Rhabdomyosarcoma - therapy; Sarcoma; Science; Science (multidisciplinary); Simplexvirus - physiology; Soft tissue sarcoma; Solid tumors; Survival Analysis; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-02503-8

Oncolytic virotherapy is an effective immunotherapeutic approach for cancer treatment via a multistep process including direct tumor cell lysis, induction of cytotoxic or apoptosis-sensitizing cytokines and promotion of antitumor T cell responses. Solid tumors limit the effectiveness of immunotherapeutics in diverse ways such as secretion of immunosuppressive cytokines and expression of immune inhibitory ligands to inhibit antitumor T cell function. Blocking programmed cell death protein (PD)-1 signaling, which mediates T cell suppression via engagement of its inhibitory ligands, PD-L1 or PD-L2, is of particular interest due to recent successes in many types of cancer. In syngeneic murine rhabdomyosarcoma models, we found that M3-9-M (MHC I high) but not 76-9 (MHC I low) tumors respond to oncolytic herpes simplex virus-1 (oHSV-1) and PD-1 blockade combination therapy. In addition, the therapeutic outcomes in M3-9-M tumor models correlated with the increased incidence of CD4 + and CD8 + T cells but not with the CD4 + CD25 + Foxp3 + regulatory T cell populations in the tumor. Overall, our data suggest the combination of PD-1 blockade and oHSV-1 may be an effective treatment strategy for childhood soft tissue sarcoma.