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Plasmacytoid dendritic cells in the tumor microenvironment: immune targets for glioma therapeutics
Marianela Candolfi1, Gwendalyn D King, Kader Yagiz
1Gene Therapeutics Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA.
Abstract:
Adenovirus-mediated delivery of the immune-stimulatory cytokine Flt3L and the conditionally cytotoxic thymidine kinase (TK) induces tumor regression and long-term survival in preclinical glioma (glioblastoma multiforme [GBM]) models. Flt3L induces expansion and recruitment of plasmacytoid dendritic cells (pDCs) into the brain. Although pDCs can present antigen and produce powerful inflammatory cytokines, that is, interferon α (IFN-α), their role in tumor immunology remains debated. Thus, we studied the role of pDCs and IFN-α in Ad.TK/GCV+ Ad.Flt3L-mediated anti-GBM therapeutic efficacy. Our data indicate that the combined gene therapy induced recruitment of plasmacytoid DCs (pDCs) into the tumor mass; which were capable of in vivo phagocytosis, IFN-α release, and T-cell priming. Thus, we next used either pDCs or an Ad vector encoding IFN-α delivered within the tumor microenvironment. When rats were treated with Ad.TK/GCV in combination with pDCs or Ad-IFN-α, they exhibited 35% and 50% survival, respectively. However, whereas intracranial administration of Ad.TK/GCV + Ad.Flt3L exhibited a high safety profile, Ad-IFN-α led to severe local inflammation, with neurologic and systemic adverse effects. To elucidate whether the efficacy of the immunotherapy was dependent on IFN-α-secreting pDCs, we administered an Ad vector encoding B18R, an IFN-α antagonist, which abrogated the antitumoral effect of Ad.TK/GCV + Ad.Flt3L. Our data suggest that IFN-α release by activated pDCs plays a critical role in the antitumor effect mediated by Ad.TK/GCV + Ad.Flt3L. In summary, taken together, our results demonstrate that pDCs mediate anti-GBM therapeutic efficacy through the production of IFN-α, thus manipulation of pDCs constitutes an attractive new therapeutic target for the treatment of GBM.
Insights
Adenovirus gene therapy using Flt3L and TK effectively treats glioma by recruiting plasmacytoid dendritic cells (pDCs). These pDCs, through interferon-alpha (IFN-α) release, are crucial for the anti-tumor immune response in glioblastoma multiforme (GBM).
Area of Science:
- Immunology
- Oncology
- Gene Therapy
Background:
- Adenovirus-mediated gene therapy combining Flt3L and TK shows promise in preclinical glioblastoma multiforme (GBM) models.
- Plasmacytoid dendritic cells (pDCs) are recruited by Flt3L and can produce interferon-alpha (IFN-α), but their role in anti-GBM immunity is unclear.
- Understanding the contribution of pDCs and IFN-α is vital for optimizing gene therapy strategies against GBM.
Purpose of the Study:
- To investigate the role of pDCs and IFN-α in the therapeutic efficacy of Ad.TK/GCV + Ad.Flt3L gene therapy for GBM.
- To determine if pDCs mediate anti-GBM effects through IFN-α production.
- To assess the safety and efficacy of direct pDC or IFN-α administration in GBM treatment.
Main Methods:
- Adenovirus-mediated delivery of Flt3L and TK (Ad.TK/GCV + Ad.Flt3L) in preclinical GBM models.
- Analysis of pDC recruitment, function (phagocytosis, IFN-α release, T-cell priming) within the tumor microenvironment.
- Treatment with intratumoral pDCs or Ad-IFN-α, and administration of an IFN-α antagonist (Ad vector encoding B18R) to assess therapeutic dependency.
Main Results:
- Combined gene therapy (Ad.TK/GCV + Ad.Flt3L) successfully recruited functional pDCs into the GBM tumor mass.
- Intratumoral administration of pDCs or Ad-IFN-α resulted in significant survival benefits (35% and 50%, respectively), while Ad.TK/GCV + Ad.Flt3L showed a high safety profile.
- Blocking IFN-α signaling with B18R abrogated the anti-GBM effect of the combined gene therapy, confirming IFN-α's critical role.
Conclusions:
- Activated pDCs mediate the anti-GBM therapeutic efficacy of Ad.TK/GCV + Ad.Flt3L gene therapy through IFN-α production.
- IFN-α released by pDCs is essential for the observed anti-tumor immune response and improved survival in GBM models.
- Targeting and manipulating pDCs represents a promising therapeutic strategy for glioblastoma multiforme treatment.
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