Abstract
Interleukin-12 (IL-12) is an inflammatory cytokine that has demonstrated efficacy for cancer immunotherapy, but systemic administration has detrimental toxicities. Lentiviral transduction eliciting IL-12-producing human sarcoma for autologous reintroduction provides localized delivery for both innate and adaptive immune response augmentation. Sarcoma cell lines and primary human sarcoma samples were transduced with recombinant lentivirus engineering expression of human IL-12 (hu-IL-12). IL-12 expressing sarcomas were assessed in vitro and in vivo following implantation into humanized NSG and transgenic human IL-15 expressing (NSG.Tg(Hu-IL-15)) murine models. Lentiviral transduction (LV/hu-IL-12) of human osteosarcoma, Ewing sarcoma and rhabdomyosarcoma cell lines, as well as low-passage primary human sarcomas, engendered high-level expression of hu-IL-12. Hu-IL-12 demonstrated functional viability, eliciting specific NK cell-mediated interferon-γ (IFN-γ) release and cytotoxic growth restriction of spheroids in vitro. In orthotopic xenograft murine models, the LV/hu-IL-12 transduced human sarcoma produced detectable IL-12 and elicited an IFN-γ inflammatory immune response specific to mature human NK reconstitution in the NSG.Tg(Hu-IL-15) model while restricting tumor growth. We conclude that LV/hu-IL-12 transduction of sarcoma elicits a specific immune reaction and the humanized NSG.Tg(Hu-IL-15) xenograft, with mature human NK cells, can define in vivo anti-tumor effects and systemic toxicities. IL-12 immunomodulation through autologous tumor transduction and reintroduction merits exploration for sarcoma treatment.
Highlights
Interleukin-12 (IL-12) is an inflammatory cytokine that has demonstrated efficacy for cancer immunotherapy, but systemic administration has detrimental toxicities
For Ewing sarcoma (A673) and rhabdomyosarcoma (RD) cells, flow cytometry (FCM) for ΔLNGFR expression was unable to differentiate transduced versus control cells due to endogenous LNGFR expression (Fig. 1b,c)
In our study we successfully demonstrate that human IL-12 can be expressed in human sarcoma cell lines derived from osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma, as well as in primary sarcoma samples following lentiviral transduction (Fig. 1)
Summary
Interleukin-12 (IL-12) is an inflammatory cytokine that has demonstrated efficacy for cancer immunotherapy, but systemic administration has detrimental toxicities. Lentiviral transduction eliciting IL-12-producing human sarcoma for autologous reintroduction provides localized delivery for both innate and adaptive immune response augmentation. In orthotopic xenograft murine models, the LV/ hu-IL-12 transduced human sarcoma produced detectable IL-12 and elicited an IFN-γ inflammatory immune response specific to mature human NK reconstitution in the NSG.Tg(Hu-IL-15) model while restricting tumor growth. One strategy to augment the immune response is through the use of interleukin-12 (IL-12), a potent activator of both the innate and adaptive immune systems[3,4] This cytokine stimulates both natural killer (NK) cells and T cells toward a proinflammatory, interferon-γ (IFN-γ) producing Type 1 differentiation r esponse[5,6,7,8]. This suggests that if NK cell responses to solid tumors can be augmented, NK cell-mediated tumor clearance and a durable adaptive immune response can be elicited
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