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

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2014-09, Vol.63 (9), p.925-938
• Main Authors: Martin, Kea, Müller, Philipp, Schreiner, Jens, Prince, Spasenija Savic, Lardinois, Didier, Heinzelmann-Schwarz, Viola A., Thommen, Daniela S., Zippelius, Alfred
• Format: Article
• Language: English
• Subjects: Animals; Antigens; B7-2 Antigen - biosynthesis; B7-2 Antigen - immunology; Cancer Research; Cancer therapies; CD11 Antigens - immunology; Cell Line, Tumor; Chemotherapy; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 Antigen - immunology; Cytokines; Cytotoxicity; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Humans; Immunology; Immunotherapy; Interferon-gamma - immunology; Kinases; Lymph Nodes - drug effects; Lymph Nodes - immunology; Lymphatic system; Lymphocyte Activation - drug effects; Lymphocytes; Maytansine - analogs & derivatives; Maytansine - pharmacology; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubules - drug effects; Microtubules - metabolism; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - immunology; Oncology; Original; Original Article; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tubulin Modulators - pharmacology; Tumors
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-014-1565-4

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.