title: The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia.
abstract: Chronic lymphocytic leukemia is marked by profound defects in T-cell function. Programmed death-1 is a receptor involved in tumor-mediated immunosuppression through binding of the PD-L1 ligand. Multiparametric flow cytometry and immunohistochemistry were used to study PD-1/PD-L1 expression. Functional assays were used to determine the involvement of the PD-1/PD-L1 axis in T-cell responses. PD-1 expression by CD4(+) and CD8(+) T lymphocytes was significantly higher in 117 chronic lymphocytic leukemia patients than in 33 donors of a comparable age. CD4(+) and CD8(+) T lymphocytes from chronic lymphocytic leukemia patients displayed increased numbers of effector memory and terminally differentiated cells, respectively, when compared to controls. The number of effector memory CD4(+) and terminally differentiated CD8(+) lymphocytes positively associated with a more advanced stage of disease, treatment requirements and unfavorable genomic aberrations. Furthermore, leukemic lymphocytes expressed higher levels of PD-L1 than circulating B lymphocytes from normal donors. PD-1 and PD-L1 surface expression spiked in proliferating T and B lymphocytes, suggesting that this interaction works efficiently in activated environments. Within chronic lymphocytic leukemia proliferation centers in the lymph node, CD4(+)/PD-1(+) T lymphocytes were found to be in close contact with PD-L1(+) chronic lymphocytic leukemia cells. Lastly, functional experiments using recombinant soluble PD-L1 and blocking antibodies indicated that this axis contributes to the inhibition of IFN-γ production by CD8(+) T cells. These observations suggest that pharmacological manipulation of the PD-1/PD-L1 axis may contribute to restoring T-cell functions in the chronic lymphocytic leukemia microenvironment.
authors.affiliation: Human Genetics Foundation (HuGeF) and Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Brusa
authors.forename: Sara
authors.initials: S
authors.lastname: Serra
authors.forename: Marta
authors.initials: M
authors.lastname: Coscia
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Giovanni
authors.initials: G
authors.lastname: D'Arena
authors.forename: Luca
authors.initials: L
authors.lastname: Laurenti
authors.forename: Ozren
authors.initials: O
authors.lastname: Jaksic
authors.forename: Giorgio
authors.initials: G
authors.lastname: Fedele
authors.forename: Giorgio
authors.initials: G
authors.lastname: Inghirami
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Fabio
authors.initials: F
authors.lastname: Malavasi
authors.forename: Silvia
authors.initials: S
authors.lastname: Deaglio
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication; D002454:Cell Differentiation; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D016176:T-Lymphocyte Subsets / Q000378:metabolism* / Q000473:pathology
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma