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Ibrutinib therapy releases leukemic surface IgM from antigen drive in chronic lymphocytic leukemia patients

Ibrutinib therapy releases leukemic surface IgM from antigen drive in chronic lymphocytic leukemia patients
Ibrutinib therapy releases leukemic surface IgM from antigen drive in chronic lymphocytic leukemia patients
Purpose: in chronic lymphocytic leukemia (CLL), disease progression associates with surface IgM (sIgM) levels and signaling capacity. These are variably down-modulated in vivo and recover in vitro, suggesting a reversible influence of tissue-located antigen. Therapeutic targeting of sIgM function via ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK), causes inhibition and tumor cell redistribution into the blood, with significant clinical benefit. Circulating CLL cells persist in an inhibited state, offering a tool to investigate the effects of drug on BTK-inhibited sIgM.

Experimental Design: we investigated the consequences of ibrutinib therapy on levels and function of sIgM in circulating leukemic cells of CLL patients.

Results: at week 1, there was a significant increase of sIgM expression (64% increase from pre-therapy) on CLL cells either recently released from tissue or persisting in blood. In contrast, sIgD and a range of other receptors, did not change. SIgM levels remained higher than pre-therapy in the following 3 months, despite gradual cell size reduction and ongoing autophagy and apoptotic activity. Conversely, IgD and other receptors did not increase and gradually declined. Recovered sIgM was fully N-glycosylated, another feature of escape from antigen, and expression did not increase further during culture in vitro. The sIgM was fully capable of mediating phosphorylation of SYK which lies upstream of BTK in the B-Cell Receptor pathway.

Conclusions: this specific IgM increase in patients underpins the key role of tissue-based engagement with antigen in CLL, confirms the inhibitory action of ibrutinib, and reveals dynamic adaptability of CLL cells to precision monotherapy.
1078-0432
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Drennan, Samantha J
dabbbebf-d205-408a-b85e-bd17a3bd4968
Chiodin, Giorgia
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D'Avola, Annalisa
26f132e6-7a6c-436c-be25-0dbff4bdb7f6
Tracy, Ian
38b326f8-e8c6-4a86-8e6c-35bebe110f9f
Johnson, Peter
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Trentin, Livio
457595df-2d40-4392-931c-3919eb5620ec
Steele, Andrew
4349f6aa-2e3a-49a8-be73-7716056ae089
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Stevenson, Freda
ba803747-c0ac-409f-a9c2-b61fde009f8c
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Drennan, Samantha J
dabbbebf-d205-408a-b85e-bd17a3bd4968
Chiodin, Giorgia
4b3e9525-b377-4d16-b69a-e05d2e7854fe
D'Avola, Annalisa
26f132e6-7a6c-436c-be25-0dbff4bdb7f6
Tracy, Ian
38b326f8-e8c6-4a86-8e6c-35bebe110f9f
Johnson, Peter
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Trentin, Livio
457595df-2d40-4392-931c-3919eb5620ec
Steele, Andrew
4349f6aa-2e3a-49a8-be73-7716056ae089
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Stevenson, Freda
ba803747-c0ac-409f-a9c2-b61fde009f8c

Forconi, Francesco, Drennan, Samantha J, Chiodin, Giorgia, D'Avola, Annalisa, Tracy, Ian, Johnson, Peter, Trentin, Livio, Steele, Andrew, Packham, Graham and Stevenson, Freda (2018) Ibrutinib therapy releases leukemic surface IgM from antigen drive in chronic lymphocytic leukemia patients. Clinical Cancer Research.

Record type: Article

Abstract

Purpose: in chronic lymphocytic leukemia (CLL), disease progression associates with surface IgM (sIgM) levels and signaling capacity. These are variably down-modulated in vivo and recover in vitro, suggesting a reversible influence of tissue-located antigen. Therapeutic targeting of sIgM function via ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK), causes inhibition and tumor cell redistribution into the blood, with significant clinical benefit. Circulating CLL cells persist in an inhibited state, offering a tool to investigate the effects of drug on BTK-inhibited sIgM.

Experimental Design: we investigated the consequences of ibrutinib therapy on levels and function of sIgM in circulating leukemic cells of CLL patients.

Results: at week 1, there was a significant increase of sIgM expression (64% increase from pre-therapy) on CLL cells either recently released from tissue or persisting in blood. In contrast, sIgD and a range of other receptors, did not change. SIgM levels remained higher than pre-therapy in the following 3 months, despite gradual cell size reduction and ongoing autophagy and apoptotic activity. Conversely, IgD and other receptors did not increase and gradually declined. Recovered sIgM was fully N-glycosylated, another feature of escape from antigen, and expression did not increase further during culture in vitro. The sIgM was fully capable of mediating phosphorylation of SYK which lies upstream of BTK in the B-Cell Receptor pathway.

Conclusions: this specific IgM increase in patients underpins the key role of tissue-based engagement with antigen in CLL, confirms the inhibitory action of ibrutinib, and reveals dynamic adaptability of CLL cells to precision monotherapy.

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Ibrutinib therapy releases leukemic surface IgM from antigen drive in chronic lymphocytic leukemia patients - Accepted Manuscript
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e-pub ahead of print date: 29 October 2018

Identifiers

Local EPrints ID: 425691
URI: https://eprints.soton.ac.uk/id/eprint/425691
ISSN: 1078-0432
PURE UUID: 9d3ba91b-0ece-4466-a2fb-36ed82c64972
ORCID for Peter Johnson: ORCID iD orcid.org/0000-0003-2306-4974
ORCID for Andrew Steele: ORCID iD orcid.org/0000-0003-0667-1596
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for Freda Stevenson: ORCID iD orcid.org/0000-0002-0933-5021

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Date deposited: 31 Oct 2018 17:30
Last modified: 02 Apr 2019 04:01

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