Barbarino, Verena, Henschke, Sinika, Blakemore, Stuart James ORCID: 0000-0003-2892-1162, Izquierdo, Elena ORCID: 0000-0002-3355-2798, Michalik, Michael, Nickel, Nadine, Moellenkotte, Indra, Vorholt, Daniela, Mueller, Linda, Brinker, Reinhild, Fedorchenko, Oleg, Mikhael, Nelly, Seeger-Nukpezah, Tamina, Hallek, Michael and Pallasch, Christian P. ORCID: 0000-0001-5675-6905 (2020). Macrophage-Mediated Antibody Dependent Effector Function in Aggressive B-Cell Lymphoma Treatment is Enhanced by Ibrutinib via Inhibition of JAK2. Cancers, 12 (8). BASEL: MDPI. ISSN 2072-6694

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Abstract

Targeted inhibition of Bruton's Tyrosine Kinase (BTK) with ibrutinib and other agents has become important treatment options in chronic lymphocytic leukemia, Waldenstrom'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(-/-)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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Barbarino, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henschke, SinikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blakemore, Stuart JamesUNSPECIFIEDorcid.org/0000-0003-2892-1162UNSPECIFIED
Izquierdo, ElenaUNSPECIFIEDorcid.org/0000-0002-3355-2798UNSPECIFIED
Michalik, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nickel, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moellenkotte, IndraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vorholt, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, LindaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brinker, ReinhildUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fedorchenko, OlegUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mikhael, NellyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seeger-Nukpezah, TaminaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pallasch, Christian P.UNSPECIFIEDorcid.org/0000-0001-5675-6905UNSPECIFIED
URN: urn:nbn:de:hbz:38-349798
DOI: 10.3390/cancers12082303
Journal or Publication Title: Cancers
Volume: 12
Number: 8
Date: 2020
Publisher: MDPI
Place of Publication: BASEL
ISSN: 2072-6694
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHRONIC LYMPHOCYTIC-LEUKEMIA; KINASE INHIBITORS; RITUXIMABMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34979

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