title: The microtubule-depolymerizing agent ansamitocin P3 programs dendritic cells toward enhanced anti-tumor immunity.
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.
authors.affiliation: Cancer Immunology and Biology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
authors.forename: Kea
authors.initials: K
authors.lastname: Martin
authors.forename: Philipp
authors.initials: P
authors.lastname: Müller
authors.forename: Jens
authors.initials: J
authors.lastname: Schreiner
authors.forename: Spasenija Savic
authors.initials: SS
authors.lastname: Prince
authors.forename: Didier
authors.initials: D
authors.lastname: Lardinois
authors.forename: Viola A
authors.initials: VA
authors.lastname: Heinzelmann-Schwarz
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Thommen
authors.forename: Alfred
authors.initials: A
authors.lastname: Zippelius
mesh_terms: D000818:Animals; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000276:immunology; D018845:CD11 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008453:Maytansine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: D051940:B7-2 Antigen; D018845:CD11 Antigens; D060908:CTLA-4 Antigen; D061026:Programmed Cell Death 1 Receptor; D050257:Tubulin Modulators; D008453:Maytansine; C015682:ansamitocins; D007371:Interferon-gamma