Abstract
The induction of antitumor immune responses in tumor-bearing hosts depends on efficient uptake and processing of native or modified tumors/self-antigens by dendritic cells (DCs) to activate immune effector cells, as well as the extent of the immunosuppressive network in the tumor microenvironment (TME). Because the C-X-C motif chemokine receptor 4 (CXCR4) for the C-X-C motif chemokine 12 (CXCL12) is involved in signaling interactions between tumor cells and their TME, we used oncolytic virotherapy with a CXCR4 antagonist to investigate whether targeting of the CXCL12/CXCR4 signaling axis in murine neuroblastoma cells (NXS2)-bearing syngeneic mice affects the efficacy of bone marrow (BM)-derived DCs loaded with autologous tumor cells treated with doxorubicin for induction of immunogenic cell death. Here, we show that CXCR4 antagonist expression from an oncolytic vaccinia virus delivered intravenously to mice with neuroblastoma tumors augmented efficacy of the DC vaccines compared to treatments mediated by a soluble CXCR4 antagonist or oncolysis alone. This study is the first demonstration that modulating the tumor microenvironment by an armed oncolytic virus could have a significant impact on the efficacy of DC vaccines, leading to the generation of effective protection against neuroblastoma challenge.
Highlights
Neuroblastoma (NB) is a usually poorly differentiated neoplasm which originates from neural crest cells and has high potential for metastasis
As the capacity of apoptotic tumor cells to trigger the immune response was found to depend on surface exposure of CRT that confers immunogenicity to otherwise nonimmunogenic cell death, allowing for an optimal anticancer chemotherapy [31], we analyzed the effect of Dox-induced cell death on cell surface expression of CRT in NXS2 neuroblastoma tumors
In view of the established role of surface CRT as an “eat me” signal [39,40], we investigated the phagocytosis of the treated tumor cells by bone marrow (BM)-derived dendritic cells (DCs), a condition that is required for mounting immune response against dying tumor cells [41]
Summary
Neuroblastoma (NB) is a usually poorly differentiated neoplasm which originates from neural crest cells and has high potential for metastasis. It is one of the most common malignancies among infants and young children. The uniqueness of NB lies in its significant heterogeneity In some patients it can undergo spontaneous regression despite the high expansion of the disease, whereas it can show a very aggressive behavior resulting in a poor long-term survival rate in others [1,2]. One of the prognosis factors for NB is the infiltration of tumor cells to bone marrow (BM) This usually indicates an advanced stage of the disease and is associated with a poor prognosis [3,4]. The C-X-C motif chemokine receptor 4 (CXCR4) expression has been shown in tumors associated with BM metastases such as Viruses 2018, 10, 455; doi:10.3390/v10090455 www.mdpi.com/journal/viruses
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