Martin, Kea Simone. Microtubule-depolymerizing agents potentiate anti-tumor immunity by stimulation of dendritic cells. 2015, PhD Thesis, University of Basel, Faculty of Science.
Restricted to Repository staff only until 21 November 2017.
Available under License CC BY-SA (Attribution-ShareAlike).
Official URL: http://edoc.unibas.ch/diss/DissB_11580
Underlining the requirement of an intact host immune system for the full therapeutic benefit of specific MDAs, the antitumor effect was far less pronounced in immunocompromised mice. Moreover, substantial therapeutic synergies were observed when combining MDAs with immunotherapy such as tumor-antigen-specific vaccination or blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death ligand 1 (PD-L1) co-inhibitory pathways. Of note, combined T cell checkpoint inhibition and MDA treatment resulted in an increased intratumoral effector T cell to regulatory T cell ratio that is associated with beneficial prognosis in multiple tumor entities. Importantly, synthetic analogues of dolastatins and maytansines are currently used as cytotoxic payloads of the two recently approved antibody-drug conjugates (ADC) brentuximab vedotin and trastuzumab-emtansine (T-DM1), respectively. Treatment with ADCs coupled to microtubule-destabilizing agents induced DC homing in murine models and activated cellular antitumor immune responses in patients, thereby demonstrating the immune-modulating potential of these ADCs.
Ultimately, these data shed light on the MDA-triggered molecular pathways that, when activated in DCs, result in inflammatory responses. We here propose that MDA-mediated microtubule disassembly triggers the release of the microtubule-associated nucleotide exchange factor GEF-H1 from its cytoskeletal anchor. Subsequent induction the small GTPase RhoA results in activation of mitogen-activated protein kinases (MAPKs) including the c-Jun N terminal kinases (JNK). Phenotypic and functional DC maturation is then mediated by JNK-dependent phosphorylation of the transcription factor c-Jun, leading to activator protein -1 (AP-1) target gene expression.
Hence, by providing the molecular basis that links microtubule disruption with triggering of innate immune responses that translate into adaptive anti-tumor immunity, we reveal a novel mechanism of action for MDAs and provide a strong rationale for clinical treatment regimens combining MDA-based therapies with immune-based therapies.
|Advisors:||Zippelius, Alfred and Finke, Daniela|
|Faculties and Departments:||03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Cancer Immunology and Biology (Zippelius/Rochlitz)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||1 Online-Ressource (146 Seiten)|
|Last Modified:||30 Jun 2016 10:59|
|Deposited On:||12 Apr 2016 13:02|
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