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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

Long-Term Ibrutinib Therapy Reverses CD8+ T Cell Exhaustion in B Cell Chronic Lymphocytic Leukaemia Thumbnail


Authors

Helen M. Parry

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.

Citation

Parry, H. M., Mirajkar, N., Cutmore, N., Zuo, J., Long, H., Kwok, M., …Moss, P. (2019). Long-Term Ibrutinib Therapy Reverses CD8+ T Cell Exhaustion in B Cell Chronic Lymphocytic Leukaemia. Frontiers in Immunology, 10, 1-7. https://doi.org/10.3389/fimmu.2019.02832

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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