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

Autor: Tina McSkeane, Jianmin Zuo, Heather M. Long, Chris Hudson, Jusnara Begum, Ceri Oldrieve, Natasha Cutmore, Guy Pratt, Marwan Kwok, Nikhil Mirajkar, Helen Parry, Paul Moss, Melanie Kelly, Shankara Paneesha, Tatjana Stankovic
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Herpesvirus 4
Human

medicine.medical_treatment
Cytomegalovirus
CD8-Positive T-Lymphocytes
chemistry.chemical_compound
0302 clinical medicine
Piperidines
Cytotoxic T cell
Medicine
Immunology and Allergy
EBV—epstein-barr virus
Original Research
biology
Middle Aged
3. Good health
Treatment Outcome
Cytokine
medicine.anatomical_structure
Ibrutinib
Female
immunotherapy
lcsh:Immunologic diseases. Allergy
CD3
T cell
Immunology
CD8 T cells
chronic lymphocytic leukaemia (CLL)
03 medical and health sciences
Immune system
herpes viruses
ibrutinib
exhaustion
Humans
Protein Kinase Inhibitors
Aged
Duration of Therapy
business.industry
Adenine
Immunotherapy
Leukemia
Lymphocytic
Chronic
B-Cell

Pyrimidines
030104 developmental biology
chemistry
biology.protein
Pyrazoles
Peptides
lcsh:RC581-607
business
Biomarkers
CD8
030215 immunology
Zdroj: Frontiers in Immunology, Vol 10 (2019)
Frontiers in Immunology
ISSN: 1664-3224
DOI: 10.3389/fimmu.2019.02832
Popis: 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.
Databáze: OpenAIRE
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