Expression of a soluble IL-10 receptor enhances the therapeutic effects of a papillomavirus-associated antitumor vaccine in a murine model

Abstract

The presence of IL-10, produced either by tumor cells or immunosuppressive cells, is frequently associated with a poor prognosis for cancer progression. It may also negatively impact anticancer treatments, such as immunotherapies, that otherwise would promote the activation of cytotoxic T cells capable of detecting and destroying malignant cells. In the present study, we evaluated a new adjuvant approach for anticancer immunotherapy using a plasmid vector encoding a soluble form of the IL-10 receptor (pIL-10R). pIL-10R was coadministered to mice with a DNA vaccine encoding the type 16 human papillomavirus (HPV-16) E7 oncoprotein genetically fused with glycoprotein D of herpes simplex virus (HSV) (pgDE7h). Immunization regimens based on the coadministration of pIL-10R and pgDE7h enhanced the antitumor immunity elicited in mice injected with TC-1 cells, which express HPV-16 oncoproteins. The administration of the DNA vaccines by in vivo electroporation further enhanced the anticancer effects of the vaccines, leading to the activation of tumor-infiltrating polyfunctional E7-specific cytotoxic CD8 + T cells and control of the expansion of immunosuppressive cells. In addition, the combination of immunotherapy and pIL-10R allowed the control of tumors in more advanced growth stages that otherwise would not be treatable by the pgDE7h vaccine. In conclusion, the proposed treatment involving the expression of IL-10R enhanced the antitumor protective immunity induced by pgDE7h administration and may contribute to the development of more efficient clinical interventions against HPV-induced tumors.

A therapeutic DNA vaccine and gemcitabine act synergistically to eradicate HPV-associated tumors in a preclinical model

“…Nonetheless, without any other associated therapy, such effects drop significantly in mice with established tumors following the engraftment of TC-1 cells, a fast-growing tumor cell line. 23 In the present study, the combination of pgDE7h EP with Gem resulted in enhanced antitumour activities in mice with established tumors, including activation of tumor-specific CTL responses. In order to demonstrate the synergic adjuvant effects of Gem when combined with immunotherapy, we selected a suboptimal dose of (80 mg/kg) in a two-dose treatment regimen (significantly lower than the dose used in patients -120 mg/kg), based on previously reported preclinical conditions.…”

“…36,42 The inhibitory effects of Gem on these cells may contribute to the tumor protection observed in mice subjected to combination therapy based on pgDE7h. Indeed, our own previous observations clearly demonstrated that the combination of active immunotherapies with blockade of immunosuppressive mechanisms, such as neutralization of IL-10, inhibition of IDO, or depletion of MDSCs, 23,24,43,44 represents a trend toward the development of treatments capable of controlling HPV-associated tumors, particularly at advanced growth stages.…”

“…21,22 Previous results demonstrated that administration of this vaccine therapeutically induced the activation of E7-specific CD8 + T cells and antitumour protection against early-stage tumors in mice. [22][23][24] In the present study, we focused on the combination of Gem and pgDE7h, aiming to improve the treatment efficacy, particularly against tumors in more advanced stages of development. Our results demonstrated the synergistic antitumour effects of the combined therapy with simultaneous control of immunosuppressive responses, induction of tumor-specific cytotoxic CD8 + T cells, and complete eradication of established tumors at experimental conditions.…”

Targeting interleukin-10 signalling for cancer immunotherapy, a promising and complicated task

“…11 Vaccination with simultaneous IL-10 signaling blockade better inhibits tumor growth Immunization and simultaneously blocking IL-10 using IL-10 receptor monoclonal antibodies drastically increase vaccineinduced antigen-specific CD8 + T cell responses, regardless the immunogen is composed of virus-like particles, peptides, soluble antigens, or nucleotides (Table 1). 10,[18][19][20] The enhanced vaccineinduced T cell responses can also be achieved by using soluble IL-10 receptor, 21 peptide-based IL-10 receptor antagonist, 22,43 or oligonucleotides. 23 Subcutaneous administration of anti-IL-10 receptor antibodies together with a vaccine, instead of intraperitoneal injection of anti-IL-10 antibodies, also elicits stronger antigen-specific CD8 + T cell responses, yet at a much lower magnitude.…”

Therapeutic vaccines for human papillomavirus-related cancer: progress and challenges

“…These vaccines are based on the production of a hybrid protein formed by the fusion of Herpes simplex virus-1 (HSV-1) glycoprotein Editorial Therapeutic vaccines for human papillomavirus-related cancer: progress and challenges D (gD) and the HPV 16 E7 oncoprotein (gDE7), which activate CD8 + E7-specific T cells and elicit a significant antitumor response in mice models. When combined with other techniques such as electroporation (10), IDO inhibitors (9), melatonin (9), polyinosinic:polycytidylic acid [poly(I:C)] (20), spores (11), chemotherapies (7,8), and IL-10 inhibitors (21), the antitumor potential of gDE7-based vaccines was boosted.…”