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.

Turmeric enhancing anti-tumor effect of Rhizoma paridis saponins by influencing their metabolic profiling in tumors of H22 hepatocarcinoma mice

“…In (Figure 1), which induced dendritic cells in priming robust immune responses in tumor-bearing hosts [17].…”

Trial watch: Dendritic cell-based anticancer immunotherapy

“…While summarizing all of these studies here is not possible, we found the following ones to be of particular interest and, in some cases, largely representing the general trends in this field (not mentioned in any particular order): (1) Mitchell et al documented that pre-conditioning the intended site for DC-based vaccination with the tetanus/diphtheria toxoid (acting as a "recall antigen") significantly improves the lymph nodehoming of DCs thereby inducing (CCL3-dependent) anti-glioblastoma immunity following DC-based vaccination in mice and patients; 185 (2) Carreno et al reported that a DC-based vaccine boosts (naturally-occurring) neoantigen-specific antimelanoma immunity (comprising an increase in diversity and clonality of neoantigen-specific T cells) associated with de novo emergence of MHC class I-restricted neoantigens; 186 (3) Garg et al found that next-generation DC-based vaccines relying on immunogenic cell death (ICD) elicited by hypericin-dependent photodynamic therapy (Hyp-PDT) in glioma cells induce potent anti-glioblastoma immunity in an orthotopic murine model (both in prophylactic and curative settings, alone or in combination with chemotherapy), accompanied by a shift from a Tregdominated intracranial immune contexture to a Th1/Th17/ CTLs-dominated one; 187 (4) Ohshio et al observed that targeting immunosuppressive cancer-associated fibroblasts with an anti-fibrotic agent, tranilast, in combination with DC-based vaccination drastically improves (CTL-and NK-cell-driven) antitumor immunity against subcutaneously transplanted lymphomas, lung carcinomas and melanomas; 188 (5) Xiang et al documented that ovalbumin-loaded upconversion nanoparticles (i.e., nanoparticles exhibiting photon upconversion, a process wherein two or more photons of low energy are absorbed and converted into a single emitted photon of higher energy) can be used for antigen loading and maturation of DCs, which can also be tracked in vivo (via luminescence imaging), so that these DCs eventually drive potent ovalbumin-specific immunity; 189 194 and (11) Martin et al discovered that ansamitocin P3, a microtubule depolymerizing agent, enhances DC activation thereby making DC-based vaccines potent inducers of antigen-specific T cells, especially in combination with ICBs targeting programmed cell death 1 (PDCD1, also known as PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4). 195 …”

Requirement of Mucosa‐Associated Lymphoid Tissue Lymphoma Translocation Protein 1 Protease Activity for Fcγ Receptor–Induced Arthritis, but Not Fcγ Receptor–Mediated Platelet Elimination, in Mice

“…Neutrophils were enriched from BM cells using an EasySep mouse neutrophil enrichment kit (StemCell Technologies). BMDCs were generated as previously described .…”