TY  - JOUR
AU  - McClanahan, Fabienne
AU  - Riches, John C
AU  - Miller, Shaun
AU  - Day, William P
AU  - Kotsiou, Eleni
AU  - Neuberg, Donna
AU  - Croce, Carlo M
AU  - Capasso, Melania
AU  - Gribben, John G
TI  - Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model.
JO  - Blood
VL  - 126
IS  - 2
SN  - 0006-4971
CY  - Washington, DC
PB  - American Society of Hematology
M1  - DZNE-2023-00629
SP  - 212 - 221
PY  - 2015
AB  - 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.
KW  - Aging: genetics
KW  - Aging: immunology
KW  - Animals
KW  - B7-H1 Antigen: physiology
KW  - CD8-Positive T-Lymphocytes: immunology
KW  - Cell Differentiation: genetics
KW  - Cell Differentiation: immunology
KW  - Cells, Cultured
KW  - Disease Models, Animal
KW  - Immunoglobulin mu-Chains: genetics
KW  - Leukemia, Lymphocytic, Chronic, B-Cell: genetics
KW  - Leukemia, Lymphocytic, Chronic, B-Cell: immunology
KW  - Leukemia, Lymphocytic, Chronic, B-Cell: pathology
KW  - Mice
KW  - Mice, Transgenic
KW  - Programmed Cell Death 1 Receptor: physiology
KW  - Proto-Oncogene Proteins: genetics
KW  - Signal Transduction: immunology
KW  - B7-H1 Antigen (NLM Chemicals)
KW  - Cd274 protein, mouse (NLM Chemicals)
KW  - Immunoglobulin mu-Chains (NLM Chemicals)
KW  - Pdcd1 protein, mouse (NLM Chemicals)
KW  - Programmed Cell Death 1 Receptor (NLM Chemicals)
KW  - Proto-Oncogene Proteins (NLM Chemicals)
KW  - Tcl1 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25979947
C2  - pmc:PMC4497962
DO  - DOI:10.1182/blood-2015-02-626754
UR  - https://pub.dzne.de/record/258656
ER  -