Abstract
Treatment of castration-resistant prostate cancer remains a challenging clinical problem. Despite the promising effects of immunotherapy in other solid cancers, prostate cancer has remained largely unresponsive. Oncolytic viruses represent a promising therapeutic avenue, as oncolytic virus treatment combines tumour cell lysis with activation of the immune system and mounting of effective anti-tumour responses. Mammalian Orthoreoviruses are non-pathogenic human viruses with a preference of lytic replication in human tumour cells. In this study, we evaluated the oncolytic efficacy of the bioselected oncolytic reovirus mutant jin-3 in multiple human prostate cancer models. The jin-3 reovirus displayed efficient infection, replication, and anti-cancer responses in 2D and 3D prostate cancer models, as well as in ex vivo cultured human tumour slices. In addition, the jin-3 reovirus markedly reduced the viability and growth of human cancer cell lines and patient-derived xenografts. The infection induced the expression of mediators of immunogenic cell death, interferon-stimulated genes, and inflammatory cytokines. Taken together, our data demonstrate that the reovirus mutant jin-3 displays tumour tropism, and induces potent oncolytic and immunomodulatory responses in human prostate cancer models. Therefore, jin-3 reovirus represents an attractive candidate for further development as oncolytic agent for treatment of patients with aggressive localised or advanced prostate cancer.
Highlights
Prostate carcinoma is the second most common cancer and the fifth leading cause of cancer-related death in men worldwide [1]
We evaluated the oncolytic efficacy of the bioselected oncolytic reovirus mutant jin3 in multiple human prostate cancer models
The wild-type reovirus type 3 Dearing (T3D) (ATCC, Manassas, VA, United States) Three days post exposure, the tissues were fixed with 4% PFA and on HER911 cells [10, 16]
Summary
Prostate carcinoma is the second most common cancer and the fifth leading cause of cancer-related death in men worldwide [1]. Accumulating evidence suggests that prostate cancer cells escape from immune surveillance by creating an immunesuppressive and immune-exclusive tumour microenvironment [4]. This immunosuppressive barrier impairs the generation and maintenance of a clinically desired anti-tumour immune response. Treatment modalities that overcome this immunosuppressive state could represent a promising option for prostate cancer. The direct oncolytic and indirect immunomodu- University Medical Center in accordance with the Dutch Act on latory effects of jin-3 reovirus were determined in state-of-the-art Animal experimentation and EU Directive 2010/63/EU (project preclinical prostate cancer models, including monolayer and licences from Central Authority for Scientific Procedures on Animals three-dimensional cell cultures, ex vivo cultured human prostate (CCD): AVD1160020173725 and AVD1160020187004). All mice were housed under sterile conditions in accordance with
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