title: 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.
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.
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; Department of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany;
authors.forename: Fabienne
authors.identifier: http://orcid.org/0000-0001-5521-3271
authors.initials: F
authors.lastname: McClanahan
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
authors.forename: John C
authors.initials: JC
authors.lastname: Riches
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
authors.forename: Shaun
authors.initials: S
authors.lastname: Miller
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
authors.forename: William P
authors.initials: WP
authors.lastname: Day
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
authors.forename: Eleni
authors.initials: E
authors.lastname: Kotsiou
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Donna
authors.identifier: http://orcid.org/0000-0003-2566-3145
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH; and.
authors.forename: Carlo M
authors.identifier: http://orcid.org/0000-0003-3788-1457
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Melania
authors.identifier: http://orcid.org/0000-0001-8659-9867
authors.initials: M
authors.lastname: Capasso
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
authors.forename: John G
authors.identifier: http://orcid.org/0000-0002-8505-7430
authors.initials: JG
authors.lastname: Gribben
mesh_terms: D000375:Aging / Q000235:genetics / Q000276:immunology*; D000818:Animals; D060890:B7-H1 Antigen / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007148:Immunoglobulin mu-Chains / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D007148:Immunoglobulin mu-Chains; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011518:Proto-Oncogene Proteins; C490393:Tcl1 protein, mouse