Multiple myeloma causes clonal T-cell immunosenescence: identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade
| Autor: | John Gibson, Narelle Woodland, Phoebe Joy Ho, S Yang, Derek N.J. Hart, Najah T. Nassif, Ross Brown, Claire Weatherburn, Christian E Bryant, Pasquale M Barbaro, Hayley Suen, Douglas E. Joshua |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Cancer Research Telomerase Immunosenescence T cell T-Lymphocytes Programmed Cell Death 1 Receptor Smad Proteins Biology Immunophenotyping 03 medical and health sciences 0302 clinical medicine Antigen medicine Cytotoxic T cell Humans CTLA-4 Antigen Cells Cultured CD28 Hematology Telomere Prognosis Immune checkpoint Clone Cells 030104 developmental biology medicine.anatomical_structure Oncology Immunology Cancer research Multiple Myeloma 030215 immunology Signal Transduction |
| Zdroj: | Leukemia. 30(8) |
| ISSN: | 1476-5551 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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