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

Cancer Immunol Immunother. 2014 Sep;63(9):925-38. doi: 10.1007/s00262-014-1565-4. Epub 2014 Jun 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-2 Antigen / biosynthesis
  • B7-2 Antigen / immunology
  • CD11 Antigens / immunology
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / immunology
  • Cell Line, Tumor
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology
  • Humans
  • Interferon-gamma / immunology
  • Lymph Nodes / drug effects
  • Lymph Nodes / immunology
  • Lymphocyte Activation / drug effects
  • Maytansine / analogs & derivatives*
  • Maytansine / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microtubules / drug effects
  • Microtubules / metabolism
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / immunology*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Tubulin Modulators / pharmacology*


  • B7-2 Antigen
  • CD11 Antigens
  • CTLA-4 Antigen
  • Programmed Cell Death 1 Receptor
  • Tubulin Modulators
  • Maytansine
  • ansamitocins
  • Interferon-gamma