Antigen Delivery to DEC205⁺ Dendritic Cells Induces Immunological Memory and Protective Therapeutic Effects against HPV-Associated Tumors at Different Anatomical Sites

Abstract

The generation of successful anticancer vaccines relies on the ability to induce efficient and long-lasting immune responses to tumor antigens. In this scenario, dendritic cells (DCs) are essential cellular components in the generation of antitumor immune responses. Thus, delivery of tumor antigens to specific DC populations represents a promising approach to enhance the efficiency of antitumor immunotherapies. In the present study, we employed antibody-antigen conjugates targeting a specific DC C-type lectin receptor. For that purpose, we genetically fused the anti-DEC205 monoclonal antibody to the type 16 human papillomavirus (HPV-16) E7 oncoprotein to create a therapeutic vaccine to treat HPV-associated tumors in syngeneic mouse tumor models. The therapeutic efficacy of the αDEC205-E7 mAb was investigated in three distinct anatomical tumor models (subcutaneous, lingual and intravaginal). The immunization regimen comprised two doses of the αDEC205-E7 mAb coadministered with a DC maturation stimulus (Polyinosinic:polycytidylic acid, poly (I:C)) as an adjuvant. The combined immunotherapy produced robust antitumor effects on both the subcutaneous and orthotopic tumor models, stimulating rapid tumor regression and long-term survival. These outcomes were related to the activation of tumor antigen-specific CD8 + T cells in both systemic compartments and lymphoid tissues. The αDEC205-E7 antibody plus poly (I:C) administration induced long-lasting immunity and controlled tumor relapses. Our results highlight that the delivery of HPV tumor antigens to DCs, particularly via the DEC205 surface receptor, is a promising therapeutic approach, providing new opportunities for the development of alternative immunotherapies for patients with HPV-associated tumors at different anatomical sites.

Interleukin-6 and indoleamine-2,3-dioxygenase as potential adjuvant targets for Papillomavirus-related tumors immunotherapy

“…(B-D) Data represent means ± SD from two (groups IL-6 -/and IL-6 -/-+ gDE7) (n=6, total n=12) or three (groups IL-6 -/-+ gDE7 + 1MT) (n=6 or 7, total n=19) independently performed experiments with comparable results and analyzed by ANOVA or by Kaplan-Meyer test (exclusively for survival assay). The antitumor effects of gDE7 combined with 1MT isoforms were followed by (B) tumor volume ( platform was designed to deliver E7 oncoprotein to DEC205 + dendritic cells (aDEC205-E7 mAb) (39). Although gDE7-based vaccines showed outstanding anticancer effects, the effectiveness decreased when tumors achieved an advanced growth stage due to immunosuppressive mechanisms elicited by tumor cells (27,34,37).…”

“…The therapeutic antitumor efficacy of gDE7-based vaccines could be enhanced by combination with different adjuvant procedures, including administration by electroporation ( 33 ), combined treatments with gemcitabine ( 34 ) and cisplatin ( 26 ), the addition of poly(I:C) ( 25 , 35 ), co-expression of IL-2 ( 36 ) or IL-10 receptor ( 37 ), adsorption to Bacillus subtilis spores ( 38 ), and combination with metabolic adjuvants such as IDO inhibitors and melatonin ( 27 ). Recently, a novel antibody-based vaccine platform was designed to deliver E7 oncoprotein to DEC205 + dendritic cells (αDEC205-E7 mAb) ( 39 ). Although gDE7-based vaccines showed outstanding anticancer effects, the effectiveness decreased when tumors achieved an advanced growth stage due to immunosuppressive mechanisms elicited by tumor cells ( 27 , 34 , 37 ).…”

Governing HPV-related carcinoma using vaccines: Bottlenecks and breakthroughs

“…DC-based whole-cell HPV vaccination is a common and emerging therapeutic vaccination to treat virus-induced cancers ( 132 ). DC-based HPV vaccinations containing the HPV antigenic gene or protein acts as a natural adjuvant to induce the antigen-specific immunity and are used in cancer immunotherapy such as siRNA-transfected DCs having pro-apoptotic molecules ( 133 ).…”

STAT3 signaling modulates the immune response induced after antigen targeting to conventional type 1 dendritic cells through the DEC205 receptor

“…The αDEC205 mAb has been widely used to target antigens to cDC1 via the DEC205 receptor. Antigen targeting to cDC1 promotes Th1 and Th1-like Tfh CD4 + T cell responses after immunization ( 8 , 11 , 13 – 15 , 17 – 29 ). The αDCIR2 (33D1) mAb has been used to target antigens to cDC2.…”