Abstract
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.
Highlights
Solid tumors evade antitumor immunity by a variety of mechanisms including secretion of immunosuppressive cytokines, recruitment of suppressive immune cells and expression of T cell inhibitory ligands
Male C57BL/6 mice were implanted with 5 × 106 M3-9-M cells subcutaneously and treated with three intratumoral (i.tu.) injections of 108 pfu HSV1716 followed by intraperitoneal (i.p.) injections of anti-PD-1 antibody. (b) Tumor volumes of mice treated with anti-PD-1, HSV1716 and combined therapy were measured twice a week and plotted individually against tumor volumes recorded for control mice. (c) Kaplan-Meier survival curves for each treatment group demonstrate the improved efficacy of combining PD-1 blockade with HSV1716 virotherapy
When we compared the ratios of CD8+ T cells to T regulatory (Treg), we found that combination therapy was significantly higher than either monotherapy in the female mice (Fig. 7b)
Summary
Solid tumors evade antitumor immunity by a variety of mechanisms including secretion of immunosuppressive cytokines, recruitment of suppressive immune cells and expression of T cell inhibitory ligands. The T cell exhaustion marker, PD-1, has emerged as an effective cancer therapeutic target, for tumors that express its ligands PD-L1 and/or PD-L22. We recently exploited two explantable syngeneic mouse rhabdomyosarcoma tumor models to study herpes virus-induced T cell-mediated antitumor effects[5]. Found that both models show significant response to oHSV virotherapy in C57BL/6 hosts, despite poor tumor susceptibility to oncolytic human HSV-1 infection and replication[5]. We found that while each displayed MHC class I, surface expression of this protein was considerably higher in M3-9-M than in 76-95, 8 These models provide an ideal setting for investigating the response to T cell checkpoint inhibitors in combination with oncolytic herpes simplex virotherapy
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