Multiple myeloma causes clonal T-cell immunosenescence: identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade.
Tumour-induced dysfunction of cytotoxic T cells in patients with multiple myeloma (MM) may contribute to immune escape and be responsible for the lack of therapeutic efficacy of immune checkpoint blockade. We therefore investigated dysfunctional clonal T cells in MM and demonstrated immunosenescence but not exhaustion as a predominant feature. T-cell clones were detected in 75% of MM patients and their prognostic significance was revalidated in a new post-immunomodulatory drug cohort. The cells exhibited a senescent secretory effector phenotype: KLRG-1+/CD57+/CD160+/CD28-. Normal-for-age telomere lengths indicate that senescence is telomere independent and potentially reversible. p38-mitogen-activated protein kinase, p16 and p21 signalling pathways known to induce senescence were not elevated. Telomerase activity was found to be elevated and this may explain how normal telomere lengths are maintained in senescent cells. T-cell receptor signalling checkpoints were normal but elevated SMAD levels associated with T-cell inactivation were detected and may provide a potential target for the reversal of clonal T-cell dysfunction in MM. Low programmed death 1 and cytotoxic T-lymphocyte-associated antigen 4 expression detected on T-cell clones infers that these cells are not exhausted but suggests that there would be a suboptimal response to immune checkpoint blockade in MM. Our data suggest that other immunostimulatory strategies are required in MM.
Institute of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.|School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.
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Suen
Institute of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
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Brown
Institute of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
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Yang
Institute of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.|Sydney University Medical School, University of Sydney, Sydney, New South Wales, Australia.
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Weatherburn
Institute of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.|Sydney University Medical School, University of Sydney, Sydney, New South Wales, Australia.
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Ho
School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.
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Woodland
School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.
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Nassif
Children's Medical Research Institute, Sydney, New South Wales, Australia.
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Barbaro
Institute of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.|Sydney University Medical School, University of Sydney, Sydney, New South Wales, Australia.|Dendritic Cell Research, ANZAC Research Institute, Sydney, New South Wales, Australia.
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Bryant
Sydney University Medical School, University of Sydney, Sydney, New South Wales, Australia.|Dendritic Cell Research, ANZAC Research Institute, Sydney, New South Wales, Australia.
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Hart
Institute of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.|Sydney University Medical School, University of Sydney, Sydney, New South Wales, Australia.
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Gibson
Institute of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.|Sydney University Medical School, University of Sydney, Sydney, New South Wales, Australia.
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Joshua
D060908:CTLA-4 Antigen / Q000032:analysis; D002478:Cells, Cultured; D002999:Clone Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D016130:Immunophenotyping; D000068884:Immunosenescence / Q000276:immunology*; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology*; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis; D015398:Signal Transduction / Q000276:immunology; D051785:Smad Proteins / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016615:Telomere / Q000201:enzymology / Q000378:metabolism
D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D061026:Programmed Cell Death 1 Receptor; D051785:Smad Proteins