Macrophage-Mediated Antibody Dependent Effector Function in Aggressive B-Cell Lymphoma Treatment is Enhanced by Ibrutinib via Inhibition of JAK2
| Autor: | Linda Müller, Daniela Vorholt, Verena Barbarino, Elena Izquierdo, Tamina Seeger-Nukpezah, Michael Hallek, Reinhild Brinker, Sinika Henschke, Christian P. Pallasch, Indra Möllenkotte, Stuart Blakemore, Oleg Fedorchenko, Nadine Nickel, Michael Michalik, Nelly Mikhael |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.drug_class ruxolitinib Chronic lymphocytic leukemia macrophage Monoclonal antibody lcsh:RC254-282 Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine immune system diseases hemic and lymphatic diseases medicine Bruton's tyrosine kinase Kinase activity Monoclonal antibody therapy Janus kinase 2 biology B-cell lymphoma Ibrutinib phagocytosis ADCP medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens JAK 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis therapeutic antibody biology.protein Cancer research Tyrosine kinase |
| Zdroj: | Cancers Cancers, Vol 12, Iss 2303, p 2303 (2020) Volume 12 Issue 8 |
| ISSN: | 2072-6694 |
| Popis: | Targeted inhibition of Bruton&rsquo s Tyrosine Kinase (BTK) with ibrutinib and other agents has become important treatment options in chronic lymphocytic leukemia, Waldenströ m&rsquo s Macroglobulinemia, Mantle cell lymphoma, and non-GCB DLBCL. Clinical trials combining small molecule inhibitors with monoclonal antibodies have been initiated at rapid pace, with the biological understanding between their synergistic interactions lagging behind. Here, we have evaluated the synergy between BTK inhibitors and monoclonal antibody therapy via macrophage mediated antibody dependent cellular phagocytosis (ADCP). Initially, we observed increased ADCP with ibrutinib, whilst second generation BTK inhibitors failed to synergistically interact with monoclonal antibody treatment. Kinase activity profiling under BTK inhibition identified significant loss of Janus Kinase 2 (JAK2) only under ibrutinib treatment. We validated this potential off-target effect via JAK inhibition in vitro as well as with CRISPR/Cas9 JAK2&minus /&minus experiments in vivo, showing increased ADCP and prolonged survival, respectively. This data supports inhibition of the JAK-STAT (Signal Transducers and Activators of Transcription) signaling pathway in B-cell malignancies in combination with monoclonal antibody therapy to increase macrophage-mediated immune responses. |
| Databáze: | OpenAIRE |
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