Activation of the human immune system via toll‐like receptors by the oncolytic parvovirus H‐1

Abstract

This study aimed to investigate the function of toll-like receptors (TLRs) during oncolytic parvovirus H-1 (H-1PV)-induced human immune responses. First, the role of TLRs in the activation of the NFjB transcription factor was characterized; second, the immunologic effects of H-1PV-induced tumor cell lysates (TCL) on human antitumor immune responses were evaluated. A human ex vivo model was used to study immune responses with dendritic cells (DCs). Human embryonic kidney cells (HEK293) transfected to stably express TLRs were used as potential human DC equivalents to further investigate the role of specific TLRs during immune activation. TLR3 and TLR9 were activated by H-1PV infection, which correlated with NFjB translocation to the nucleus and a reduced cytoplasmic IjB expression. Using a TLR-signaling reporter plasmid (pNiFty-Luc), NFjB activity was increased following H-1PV infection. In addition, human DCs coincubated with H-1PV-induced TCL demonstrated increased TLR3 and TLR9 expression. These data suggest that H-1PV-induced TCL stimulate human DCs at least in part through TLR-dependent signaling pathways. Thus, DC maturation occurred through exposure to H-1PV-induced TCL through TLR-signaling leading to NFjB-dependent activation of the adaptive immune system as indicated by the increased expression of CD86, TLR3 and TLR9. Furthermore, the transcription of various cytokines indicates the activation of immune response, therefore the production of the proinflammatory cytokine TNF-a was determined. Here, H-1PV-induced TCL significantly enhanced the TNF-a level by DCs after coculture. H-1PV oncolytic virotherapy enhances immune priming by different effects on DCs and generates antitumor immunity. These findings potentially offer a new approach to tumor therapy.

Oncolytic Virotherapy as Emerging Immunotherapeutic Modality: Potential of Parvovirus H-1

“…This suggested that virus-induced TCLs contained molecular patterns triggering TLR signaling in DCs, as further evidenced by increased NF-κB levels and production of pro-inflammatory cytokines (12). Some of these immunostimulating patterns may consist of viral constituents, given the known ability of TLR3 and TLR9 for sensing viral determinants.…”

“…It is worth noting that besides their own anti-tumor efficiency, OVs can resensitize resistant tumors to chemotherapeutics, thereby highlighting the potential of OVs in multimodal treatments (12, 13). We were particularly interested in the oncolytic parvovirus H-1PV [for reviews, see Ref.…”

Complementary Induction of Immunogenic Cell Death by Oncolytic Parvovirus H-1PV and Gemcitabine in Pancreatic Cancer

“…Lysosomal and cytoplasmic sensors binding viral RNA (TLR3, protein kinase R [PKR], RIG-I, and MAVS) or ssDNA (TLR9) sequences have been shown to respond to infection with the autonomous parvoviruses MVMp and H-1PV (36,44,(97)(98)(99)(100). Notably, the cell-type-dependent pattern of sensor expression determined both induction of the IFN response and permissiveness for virus infection, accounting for the abortion of the viral life cycle in TLR3/TLR9/PKR-positive fibroblasts or immune cells and for the success of virus replication in tumor cells lacking these intracellular receptors.…”

Trial Watch:

“…Oncolytic viruses appear indeed to specifically kill transformed cells, hence releasing elevated amounts of tumor-associated antigens, and deliver to the immune system robust stimulatory signals, de facto acting as therapeutic anticancer vaccines 64 . The elevated immunogenic potential of oncolytic virotherapy presumably reflects the ability of viral components to act as microbe-associated molecular patterns, hence activating multiple pattern recognition receptors, 273 - 279 as well as to promote the emission of endogenous danger-associated molecular patterns 69 , 208 , 241 , 280 . In line with this notion, oncolytic viruses have already been shown to improve the efficacy of multiple immunotherapeutic interventions against cancer, including peptide- as well as DNA-based vaccines 75 , 77 , 281 .…”