Multiple myeloma causes clonal T-cell immunosenescence: Identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade

Suen, H; Brown, R; Yang, S; Weatherburn, C; Ho, PJ; Woodland, N; Nassif, N; Barbaro, P; Bryant, C; Hart, D; Gibson, J; Joshua, D

Multiple myeloma causes clonal T-cell immunosenescence: Identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade

Suen, H Brown, R Yang, S Weatherburn, C Ho, PJ Woodland, N Nassif, N

Barbaro, P Bryant, C Hart, D Gibson, J Joshua, D

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Publication Type:: Journal Article
Citation:: Leukemia, 2016, 30 (8), pp. 1716 - 1724
Issue Date:: 2016-08-01

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Field	Value	Language
dc.contributor.author	Suen, H	en_US
dc.contributor.author	Brown, R	en_US
dc.contributor.author	Yang, S	en_US
dc.contributor.author	Weatherburn, C	en_US
dc.contributor.author	Ho, PJ	en_US
dc.contributor.author	Woodland, N	en_US
dc.contributor.author	Nassif, N https://orcid.org/0000-0003-2675-8322	en_US
dc.contributor.author	Barbaro, P	en_US
dc.contributor.author	Bryant, C	en_US
dc.contributor.author	Hart, D	en_US
dc.contributor.author	Gibson, J	en_US
dc.contributor.author	Joshua, D	en_US
dc.date.available	2016-03-30	en_US
dc.date.issued	2016-08-01	en_US
dc.identifier.citation	Leukemia, 2016, 30 (8), pp. 1716 - 1724	en_US
dc.identifier.issn	0887-6924	en_US
dc.identifier.uri	http://hdl.handle.net/10453/90376
dc.description.abstract	© 2016 Macmillan Publishers Limited. 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.	en_US
dc.relation.ispartof	Leukemia	en_US
dc.relation.isbasedon	10.1038/leu.2016.84	en_US
dc.subject.classification	Immunology	en_US
dc.subject.mesh	T-Lymphocytes	en_US
dc.subject.mesh	Cells, Cultured	en_US
dc.subject.mesh	Clone Cells	en_US
dc.subject.mesh	Telomere	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Multiple Myeloma	en_US
dc.subject.mesh	Prognosis	en_US
dc.subject.mesh	Immunophenotyping	en_US
dc.subject.mesh	Signal Transduction	en_US
dc.subject.mesh	Smad Proteins	en_US
dc.subject.mesh	CTLA-4 Antigen	en_US
dc.subject.mesh	Programmed Cell Death 1 Receptor	en_US
dc.subject.mesh	Immunosenescence	en_US
dc.title	Multiple myeloma causes clonal T-cell immunosenescence: Identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade	en_US
dc.type	Journal Article
utslib.citation.volume	8	en_US
utslib.citation.volume	30	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	1112 Oncology and Carcinogenesis	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	open_access
pubs.issue	8	en_US
pubs.publication-status	Published	en_US
pubs.volume	30	en_US

Abstract:

© 2016 Macmillan Publishers Limited. 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.

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http://hdl.handle.net/10453/90376