Oncolytic Adenovirus Type 3 Coding for CD40L Facilitates Dendritic Cell Therapy of Prostate Cancer in Humanized Mice and Patient Samples
| Autor: | Zafar, Sadia, Basnet, Saru, Launonen, Inga-Maria, Quixabeira, Dafne Carolina Alves, Santos, Joao, Hemminki, Otto, Malmstedt, Minna, Cervera-Carrascon, Victor, Aronen, Pasi, Kalliokoski, Riikka, Havunen, Riikka, Rannikko, Antti, Mirtti, Tuomas, Matikainen, Mika, Kanerva, Anna, Hemminki, Akseli |
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| Přispěvatelé: | HUS Comprehensive Cancer Center, Department of Oncology, TRIMM - Translational Immunology Research Program, University of Helsinki, Research Programs Unit, Department of Pathology, Clinicum, HUS Helsinki and Uusimaa Hospital District, Medicum, HUS Abdominal Center, Urologian yksikkö, Department of Surgery, Helsinki University Hospital Area, Research Program in Systems Oncology, HUSLAB, University Management, HUS Gynecology and Obstetrics, Akseli Eetu Hemminki / Principal Investigator |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
11832 Microbiology and virology
318 Medical biotechnology 1184 Genetics developmental biology physiology PROGRESSION prostate cancer GENE-TRANSFER DESMOGLEIN 2 MECHANISMS PHASE-I DIFFERENTIATION adenovirus 3 dendritic cells (DCs) tumor microenvironment IMMUNE-RESPONSE VACCINATION CD40 ligand IMMUNOTHERAPY LIGAND |
| Popis: | Dendritic cell (DC)-based vaccines have shown some degree of success for the treatment of prostate cancer (PC). However, the highly immunosuppressive tumor microenvironment leads to DC dysfunction, which has limited the effectiveness of these vaccines. We hypothesized that use of a fully serotype 3 oncolytic adenovirus (Ad3-hTERT-CMV-hCD40L; TILT-234) could stimulate DCs in the prostate tumor microenvironment by expressing CD40L. Activated DCs would then activate cytotoxic T cells against the tumor, resulting in therapeutic immune responses. Oncolytic cell killing due to cancer cell-specific virus replication adds to antitumor effects but also enhances the immunological effect by releasing tumor epitopes for sampling by DC, in the presence of danger signals. In this study, we evaluated the companion effect of Ad3-hTERT-CMV-hCD40L and DC-therapy in a humanized mouse model and PC histocultures. Treatment with Ad3-hTERT-CMV-hCD40L and DC resulted in enhanced antitumor responses in vivo. Treatment of established histocultures with Ad3-hTERT-CMV-hCD40L induced DC maturation and notable increase in proinflammatory cytokines. In conclusion, Ad3-hTERT-CMV-hCD40L is able to modulate an immunosuppressive prostate tumor microenvironment and improve the effectiveness of DC vaccination in PC models and patient histocultures, setting the stage for clinical translation. |
| Databáze: | OpenAIRE |
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