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Extranodal induction of therapeutic immunity in the tumor microenvironment after intratumoral delivery of Tbet gene-modified dendritic cells

Cancer Gene Therapy volume 20, pages 469–477 (2013)Cite this article

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Abstract

Murine dendritic cells (DC) transduced to express the Type-1 transactivator T-bet (i.e. mDC.Tbet) and delivered intratumorally as a therapy are superior to control wild-type DC in slowing the growth of established subcutaneous MCA205 sarcomas in vivo. Optimal antitumor efficacy of mDC.Tbet-based gene therapy was dependent on host natural killer (NK) cells and CD8+ T cells, and required mDC.Tbet expression of major histocompatibility complex class I molecules, but was independent of the capacity of the injected mDC.Tbet to produce proinflammatory cytokines (interleukin-12 family members or interferon-γ) or to migrate to tumor-draining lymph nodes based on CCR7 ligand chemokine recruitment. Conditional (CD11c-DTR) or genetic (BATF3−/−) deficiency in host antigen-crosspresenting DC did not diminish the therapeutic action of intratumorally delivered wild-type mDC.Tbet. Interestingly, we observed that intratumoral delivery of mDC.Tbet (versus control mDC.Null) promoted the acute infiltration of NK cells and naive CD45RB+ T cells into the tumor microenvironment (TME) in association with elevated expression of NK- and T-cell-recruiting chemokines by mDC.Tbet. When taken together, our data support a paradigm for extranodal (cross)priming of therapeutic Type-1 immunity in the TME after intratumoral delivery of mDC.Tbet-based gene therapy.

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Acknowledgements

We thank Drs Todd Reinhart and Per Basse for helpful comments and information provided during the performance of this work and the drafting of this manuscript. We also thank Drs David Stroncek and Ping Jin (NIH) for performing the gene expression microarray analysis on hDC.Tbet versus control hDC. This work was supported by NIH Grants P50 CA121973, P01 CA109688 and R01 CA169118 (to WJS). This project used the UPCI’s Vector Core Facility and the Cell and Tissue Imaging Facility (CTIF) supported in part by the University of Pittsburgh CCSG award P30 CA047904. DBL was supported by a Postdoctoral Fellowship (PF-11-151-01-LIB) from the American Cancer Society.

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Authors and Affiliations

  1. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    L Chen, N C Sabins, Z You & W J Storkus

  2. Department of Dermatology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    J L Taylor, D B Lowe, Z You & W J Storkus

  3. Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Y Qu

  4. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    W J Storkus

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  1. L Chen
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Chen, L., Taylor, J., Sabins, N. et al. Extranodal induction of therapeutic immunity in the tumor microenvironment after intratumoral delivery of Tbet gene-modified dendritic cells. Cancer Gene Ther 20, 469–477 (2013). https://doi.org/10.1038/cgt.2013.42

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