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

Research output: Contribution to journalArticle

Authors

  • Nikhil Mirajkar
  • Natasha Cutmore
  • Ceri Oldrieve
  • Chris Hudson
  • Shankara Paneesha
  • Melanie Kelly
  • Jusnara Begum
  • Tina McSkeane
  • Guy Pratt
  • Paul Moss

External organisations

  • University Hospitals Birmingham NHS Foundation Trust
  • St James' University Hospital, Leeds, UK.
  • Cancer Bioinfomatics Group, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
  • Nottingham Trent University, Nottingham

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.

Bibliographic note

Copyright © 2019 Parry, Mirajkar, Cutmore, Zuo, Long, Kwok, Oldrieve, Hudson, Stankovic, Paneesha, Kelly, Begum, McSkeane, Pratt and Moss.

Details

Original languageEnglish
Article number2832
JournalFrontiers in immunology
Volume10
Publication statusPublished - 12 Dec 2019

Keywords

  • CD8 T cells, EBV—epstein-barr virus, chronic lymphocytic leukaemia (CLL), cytomegalovirus, exhaustion, herpes viruses, ibrutinib, immunotherapy