Helen M. Parry
Long-Term Ibrutinib Therapy Reverses CD8+ T Cell Exhaustion in B Cell Chronic Lymphocytic Leukaemia
Parry, Helen M.; Mirajkar, Nikhil; Cutmore, Natasha; Zuo, Jianmin; Long, Heather; Kwok, Marwan; Oldrieve, Ceri; Hudson, Chris; Stankovic, Tatjana; Paneesha, Shankara; Kelly, Melanie; Begum, Jusnara; McSkeane, Tina; Pratt, Guy; Moss, Paul
Authors
Nikhil Mirajkar
Natasha Cutmore
Jianmin Zuo
Heather Long
Marwan Kwok
Ceri Oldrieve
CHRISTOPHER HUDSON chris.hudson@nottingham.ac.uk
Professor of Dairy Herd Health and Production
Tatjana Stankovic
Shankara Paneesha
Melanie Kelly
Jusnara Begum
Tina McSkeane
Guy Pratt
Paul Moss
Abstract
Chronic Lymphocytic Leukaemia (CLL) is associated with immune suppression and susceptibility to infection. CD8+ T cell numbers are increased and demonstrate elevated expression of PD-1 and impaired function. The mechanisms driving these features of exhaustion are uncertain but are likely to include chronic immune recognition of tumor and/or infectious agents. We investigated the number, phenotype and function of total and virus-specific CD8+ T cells in 65 patients with CLL and 14 patients undergoing long-term ibrutinib therapy (median 21 months). Ibrutinib substantially reduced the number of both CD3+ T cells and CD8+ T cells. Importantly, this was associated with a reduction in PD-1 expression on CD8+ T cells (median 28 vs. 24%; p = 0.042) and 3.5 fold increase in cytokine production following mitogen stimulation. The influence of ibrutinib on antigen-specific CD8+ T cell function was assessed by HLA-peptide tetramers and revealed increased IFNγ and TNFα cytokine responses following stimulation with CMV or EBV peptides together with a 55% reduction in the frequency of “inflated” virus-specific CD8+ T cells. These findings reveal that long-term ibrutinib therapy is associated with substantial reversal of T cell exhaustion in B-CLL and is likely to contribute to the reduced infection risk seen in association with this agent.
Journal Article Type | Article |
---|---|
Acceptance Date | Nov 18, 2019 |
Online Publication Date | Dec 12, 2019 |
Publication Date | Dec 12, 2019 |
Deposit Date | Dec 18, 2019 |
Publicly Available Date | Dec 18, 2019 |
Journal | Frontiers in Immunology |
Electronic ISSN | 1664-3224 |
Publisher | Frontiers Media |
Peer Reviewed | Peer Reviewed |
Volume | 10 |
Article Number | 2832 |
Pages | 1-7 |
DOI | https://doi.org/10.3389/fimmu.2019.02832 |
Keywords | ibrutinib, chronic lymphocytic leukaemia (CLL), herpes viruses, exhaustion, EBV—epstein-barr virus, CD8 T cells, cytomegalovirus, immunotherapy |
Public URL | https://nottingham-repository.worktribe.com/output/3596943 |
Publisher URL | https://www.frontiersin.org/articles/10.3389/fimmu.2019.02832/full |
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Long-Term Ibrutinib Therapy Reverses CD8+ T Cell Exhaustion in B Cell Chronic Lymphocytic Leukaemia
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Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/
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