Herpes Simplex Virus Glycoprotein D Targets a Specific Dendritic Cell Subset and Improves the Performance of Vaccines to Human Papillomavirus-Associated Tumors

Abstract

Cervical cancer is a major public health problem and one of the leading causes of cancer deaths in women. Virtually all cases of cervical cancer, as well as a growing share of anal and head/neck tumors, are associated with human papillomavirus (HPV) infection. Despite the effectiveness, the available prophylactic vaccines do not benefit women with cervical lesions or cancer. Therefore, the search of new immunotherapeutic approaches to treat HPV-induced tumors is still a priority. The present study characterizes a therapeutic antitumor vaccine based on the genetic fusion of the Herpes simplex virus-1 (HSV-1) glycoprotein D (gD) with the E7 oncoprotein from HPV-16 (gDE7). Two subcutaneous doses of gDE7, admixed with poly (I:C), conferred complete and long-lasting therapeutic antitumor protection on mice previously challenged with tumor cells expressing the HPV-16 oncoproteins. The vaccine induced multifunctional E7-specific CD8 T cells with cytotoxic activity and effector memory phenotype (CD44 CD62L). In addition, gDE7 admixed with poly (I:C) vaccination controlled the expansion of tumor-induced regulatory T cells and myeloid-derived suppressor cells. More importantly, gDE7 activated mouse CD11c CD8α and human BDCA3 dendritic cells (DC), specialized in antigen cross-presentation to CD8 T cells, under conditions. These results indicated that the activation of a specific DC population, mediated by gD, improved the antigen-specific immune responses and the therapeutic performance induced by antitumor vaccines. These results open perspectives for the clinical testing of gDE7-based vaccines under the concept of active immunization as a tool for the therapeutic control of cancer..

The Combined Use of Melatonin and an Indoleamine 2,3-Dioxygenase-1 Inhibitor Enhances Vaccine-Induced Protective Cellular Immunity to HPV16-Associated Tumors

“…Subsequently, we evaluated the impact of IDO1 expression on the efficacy of gDE7-based immunotherapy in C57Bl/6 and isogenic IDO1 −/− mice. Seven days after TC-1 injection, mice were immunized at a suboptimal conditions ( 28 , 29 ). The vaccine was subcutaneously administered twice (7-day interval), starting 7 days after TC-1 cells challenge, a time point in which the tumors became palpable (Figure 4A ).…”

“…Wu from Johns Hopkins University in Baltimore, MD, USA. The cells were cultured as previously described ( 29 ).…”

“…All procedures for manipulation, immunization and euthanasia were approved by the ethics committee for animal experimentation (protocol number CEUA 050/2014) and followed the standard rules approved by the National Council for Control of Animal Experimentation (CONCEA). The tumor cells transplantation was performed as previously described ( 29 ), at a concentration of 1 × 10 5 cells/100 μL/animal on 0 day. Mice were considered as tumor-bearing when tumors became palpable (7–10 day) and were sacrificed when tumors exceeded 15 mm in “L” diameter.…”

“…Intracellular IFN-γ staining was performed as previously described ( 29 ). The mouse peripheral blood mononuclear cells were collected in heparin-containing vials14 days after the last gDE7 immunization (28 day).…”

“…The IDO inhibitors 1MT (enantiomers and racemic mixture) were chosen to compose our therapeutic approach based on their preclinical and clinical data as adjuvants of antitumor therapies ( 20 , 22 , 23 , 27 ). The gDE7 vaccine ( 28 , 29 ), as well as its DNA version (pgDE7h) ( 30 ), has shown excellent therapeutic effects in experimental conditions based in mice transplanted with TC-1 cells, a murine tumor cell line encoding the HPV-16 oncoproteins. We show here that IDO1 expression in immune cells and stromal cells, but not in tumor cells, impairs the antitumor effect of the gDE7 vaccine and, more relevantly, we demonstrated that combination of melatonin and an IDO inhibitor augmented the antitumor therapeutic effects of gDE7 and increased the activation of E7-specific cytotoxic CD8 + T-cell responses.…”