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 |
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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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