Differential infection of murine and human dendritic cell subsets by oncolytic vesicular stomatitis virus variants

Abstract

Oncolytic viruses (OVs) can eradicate tumor cells and elicit antitumor immunity. VSV-GP, a chimeric vesicular stomatitis virus (VSV) with the glycoprotein (GP) of the lymphocytic choriomeningitis virus, is a promising new OV candidate. However, the interaction of VSV-GP with host immune cells is not fully understood. Dendritic cells (DCs) are essential for inducing efficient antitumor immunity. Thus, we aimed to investigate the interaction of VSV-GP with different murine and human DCs subsets in direct comparison to the less cytopathic variant VSV-dM51-GP and wild type VSV. Immature murine bone marrow-derived DCs (BMDCs) were equally infected and killed by VSV and VSV-GP. Human monocyte-derived DCs (moDCs) were more permissive to VSV. Interestingly, VSV-dM51-GP induced maturation instead of killing in both BMDCs and moDCs as well as a pronounced release of pro-inflammatory cytokines. Importantly, matured BMDCs and moDCs were no longer susceptible to VSV-GP infection. Mouse splenic conventional DC type 1 (cDC1) could be infected ex vivo by VSV and VSV-GP to a higher extent than cDC2. Systemic infection of mice with VSV-GP and VSV-dM51-GP resulted in strong activation of cDCs despite low infection rates in spleen and tumor tissue. Human blood cDC1 were equally infected by VSV and VSV-GP, whereas cDC2 showed preferential infection with VSV. Our study demonstrated differential DC infection, activation, and cytokine production after the treatment with VSV and VSV-GP variants among species and subsets, which should be taken into account when investigating immunological mechanisms of oncolytic virotherapy in mouse models and human clinical trials.

Keywords: Oncolytic viruses; dendritic cells; infection; vesicular stomatitis virus.

Figure 1.

Infection of mouse BMDCs with VSV, VSV-GP, and VSV-dM51-GP

Figure 2.

VSV-GP infects and kills immature BMDCs while VSV-dM51-GP leads to maturation of BMDC cultures

Figure 3.

VSV-GP variants and VSV infect splenic conventional DCs ex vivo

Figure 4.

Infection of splenic DCs and tumor-associated DC is low in vivo but VSV-GP and VSV-dM51-GP activated the DC subsets

Figure 5.

VSV-GP variants infect human monocyte-derived immature DCs less than VSV

Figure 6.

Human blood conventional DCs can be infected by VSV-GP variants and VSV while plasmacytoid DCs are resistant to infection

Figure 7.

Different cytokine profiles are induced in murine and human DCs in response to VSV variants