Evaluation of Newcastle disease virus mediated dendritic cell activation and cross‐priming tumor‐specific immune responses ex vivo

We have developed an oncolytic Newcastle disease virus (NDV) that has potent in vitro and in vivo anti‐tumor activities and attenuated pathogenicity in chickens. In this ex vivo study using the same recombinant NDV backbone with GFP transgene (NDV‐GFP, designated as rNDV), we found that rNDV induces maturation of monocyte‐derived immature dendritic cells (iDCs) by both direct and indirect mechanisms, which promote development of antigen‐specific T cell responses. Addition of rNDV directly to iDCs culture induced DC maturation, as demonstrated by the increased expression of costimulatory and antigen‐presenting molecules as well as the production of type I interferons (IFNs). rNDV infection of the HER‐2 positive human breast cancer cell line (SKBR3) resulted in apoptotic cell death, release of proinflammatory cytokines, and danger‐associated molecular pattern molecules (DAMPs) including high‐mobility group protein B1 (HMGB1) and heat shock protein 70 (HSP70). Addition of rNDV‐infected SKBR3 cells to iDC culture resulted in greatly enhanced upregulation of the maturation markers and release of type I IFNs by DCs than rNDV‐infected DCs only. When co‐cultured with autologous T cells, DCs pre‐treated with rNDV‐infected SKBR3 cells cross‐primed T cells in an antigen‐specific manner. Altogether, our data strongly support the potential of oncolytic NDV as efficient therapeutic agent for cancer treatment. What's new? Oncolytic viruses could offer a new modality to treat metastatic cancers such as breast cancer by triggering systemic anti‐tumor immunity. In this first comprehensive ex vivo study to explore the potential of oncolytic Newcastle disease virus (NDV) in eliciting tumor‐specific CD8+ T cells, the authors demonstrate that NDV infection of breast tumor cells can trigger their immunogenic cell death, facilitate activation of dendritic cells, and allow the cross‐priming of naïve T cells into tumor‐specific T cells. The data strongly support the use of NDV in the clinical setting as a promising immunotherapeutic agent, possibly in combination with immune checkpoint inhibitors.