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The microtubule-depolymerizing agent ansamitocin P3 programs dendritic cells toward enhanced anti-tumor immunity

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Abstract

In addition to direct tumor cell cytotoxicity, chemotherapy can mediate tumor reduction through immune modulation of the tumor microenvironment to promote anti-tumor immunity. Mature dendritic cells (DCs) play key roles in priming robust immune responses in tumor-bearing hosts. Here, we screened a panel of 21 anticancer agents with defined molecular targets for their ability to induce direct maturation of DCs. We identified ansamitocin P3, a microtubule-depolymerizing agent, as a potent inducer of phenotypic and functional maturation of DCs. Exposure of both murine spleen-derived and human monocyte-derived DCs to ansamitocin P3 triggered up-regulation of maturation markers and production of pro-inflammatory cytokines, resulting in an enhanced T cell stimulatory capacity. Local administration of ansamitocin P3 induced maturation of skin Langerhans cells in vivo and promoted antigen uptake and extensive homing of tumor-resident DCs to tumor-draining lymph nodes. When used as an adjuvant in a specific vaccination approach, ansamitocin P3 dramatically increased activation of antigen-specific T cells. Finally, we demonstrate that ansamitocin P3, due to its immunomodulatory properties, acts in synergy with antibody-mediated blockade of the T cell inhibitory receptors PD-1 and CTLA-4. The combination treatment was most effective and induced durable growth inhibition of established tumors. Mechanistically, we observed a reduced regulatory T cell frequency and improved T cell effector function at the tumor site. Taken together, our study unravels an immune-based anti-tumor mechanism exploited by microtubule-depolymerizing agents, including ansamitocin P3, and paves the way for future clinical trials combining this class of agents with immunotherapy.

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Acknowledgments

This work was supported by grants from the Swiss National Science Foundation, the Wilhelm-Sander-Foundation, the Cancer League Basel, and the Huggenberger Stiftung. We thank Béatrice Dolder-Schlienger, Mélanie Buchi, and Petra Herzig for excellent technical assistance; Arne Sutter (Merck KGaA) for providing the SP37A3 cell line; the Developmental Therapeutics Program at NCI/NIH for providing ansamitocin P3, vinblastine, vindesine, and vinorelbine; Jean Pieters for providing OT-II mice; and Douglas Fearon and Mark Smyth for providing tumor cell lines. Furthermore, we thank Heinz Läubli, Narasimha Rao Uda, and Matthias Kreuzaler for critical reading of the manuscript.

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The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Cancer Immunology and Biology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland

    Kea Martin, Philipp Müller, Jens Schreiner, Daniela S. Thommen & Alfred Zippelius

  2. Institute of Pathology, University Hospital Basel, Basel, Switzerland

    Spasenija Savic Prince

  3. Department of Surgery, University Hospital Basel, Basel, Switzerland

    Didier Lardinois

  4. Department of Gynecology and Gynecologic Oncology, University Hospital Basel, Basel, Switzerland

    Viola A. Heinzelmann-Schwarz

  5. Department of Medical Oncology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland

    Daniela S. Thommen & Alfred Zippelius

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  1. Kea Martin
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  2. Philipp Müller
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K. Martin and P. Müller have contributed equally to this work.

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Martin, K., Müller, P., Schreiner, J. et al. The microtubule-depolymerizing agent ansamitocin P3 programs dendritic cells toward enhanced anti-tumor immunity. Cancer Immunol Immunother 63, 925–938 (2014). https://doi.org/10.1007/s00262-014-1565-4

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