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@ARTICLE{McClanahan:258656,
author = {McClanahan, Fabienne and Riches, John C and Miller, Shaun
and Day, William P and Kotsiou, Eleni and Neuberg, Donna and
Croce, Carlo M and Capasso, Melania and Gribben, John G},
title = {{M}echanisms of {PD}-{L}1/{PD}-1-mediated {CD}8 {T}-cell
dysfunction in the context of aging-related immune defects
in the {E}µ-{TCL}1 {CLL} mouse model.},
journal = {Blood},
volume = {126},
number = {2},
issn = {0006-4971},
address = {Washington, DC},
publisher = {American Society of Hematology},
reportid = {DZNE-2023-00629},
pages = {212 - 221},
year = {2015},
abstract = {T-cell defects, immune suppression, and poor antitumor
immune responses are hallmarks of chronic lymphocytic
leukemia (CLL), and PD-1/PD-L1 inhibitory signaling has
emerged as a major immunosuppressive mechanism. However, the
effect of different microenvironments and the confounding
influence of aging are poorly understood. The current study
uses the Eμ-TCL1 mouse model, which replicates human T-cell
defects, as a preclinical platform to longitudinally examine
patterns of T-cell dysfunction alongside developing CLL and
in different microenvironments, with a focus on PD-1/PD-L1
interactions. The development of CLL was significantly
associated with changes in T-cell phenotype across all
organs and function. Although partly mirrored in aging
wild-type mice, CLL-specific T-cell changes were identified.
Murine CLL cells highly expressed PD-L1 and PD-L2 in all
organs, with high PD-L1 expression in the spleen.
CD3(+)CD8(+) T cells from leukemic and aging healthy mice
highly expressed PD-1, identifying aging as a confounder,
but adoptive transfer experiments demonstrated CLL-specific
PD-1 induction. Direct comparisons of PD-1 expression and
function between aging CLL mice and controls identified
PD-1(+) T cells in CLL as a heterogeneous population with
variable effector function. This is highly relevant for
therapeutic targeting of CD8(+) T cells, showing the
potential of reprogramming and selective subset expansion to
restore antitumor immunity.},
keywords = {Aging: genetics / Aging: immunology / Animals / B7-H1
Antigen: physiology / CD8-Positive T-Lymphocytes: immunology
/ Cell Differentiation: genetics / Cell Differentiation:
immunology / Cells, Cultured / Disease Models, Animal /
Immunoglobulin mu-Chains: genetics / Leukemia, Lymphocytic,
Chronic, B-Cell: genetics / Leukemia, Lymphocytic, Chronic,
B-Cell: immunology / Leukemia, Lymphocytic, Chronic, B-Cell:
pathology / Mice / Mice, Transgenic / Programmed Cell Death
1 Receptor: physiology / Proto-Oncogene Proteins: genetics /
Signal Transduction: immunology / B7-H1 Antigen (NLM
Chemicals) / Cd274 protein, mouse (NLM Chemicals) /
Immunoglobulin mu-Chains (NLM Chemicals) / Pdcd1 protein,
mouse (NLM Chemicals) / Programmed Cell Death 1 Receptor
(NLM Chemicals) / Proto-Oncogene Proteins (NLM Chemicals) /
Tcl1 protein, mouse (NLM Chemicals)},
ddc = {610},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:25979947},
pmc = {pmc:PMC4497962},
doi = {10.1182/blood-2015-02-626754},
url = {https://pub.dzne.de/record/258656},
}