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

Helen M Parry, Nikhil Mirajkar, Natasha Cutmore, Jianmin Zuo, Heather Long, Marwan Kwok, Ceri Oldrieve, Chris Hudson, Tatjana Stankovic, Shankara Paneesha, Melanie Kelly, Jusnara Begum, Tina McSkeane, Guy Pratt, Paul Moss

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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.

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

Keywords

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

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