title: Stimulation of Wnt/ß-catenin pathway in human CD8+ T lymphocytes from blood and lung tumors leads to a shared young/memory phenotype.
abstract: Cancer can be treated by adoptive cell transfer (ACT) of T lymphocytes. However, how to optimally raise human T cells to a differentiation state allowing the best persistence in ACT is a challenge. It is possible to differentiate mouse CD8(+) T cells towards stem cell-like memory (T(SCM)) phenotype upon TCR stimulation with Wnt/ß-catenin pathway activation. Here, we evaluated if T(SCM) can be obtained from human mature CD8(+) T cells following TCR and Wnt/ß-catenin activation through treatment with the chemical agent 4,6-disubstituted pyrrolopyrimidine (TWS119), which inhibits the glycogen synthase kinase-3β (GSK-3β), key inhibitor of the Wnt pathway. Human CD8(+) T cells isolated from peripheral blood or tumor-infiltrating lymphocytes (TIL), and treated with TWS119 gave rise to CD62L(+)CD45RA(+) cells, indicative of early differentiated stage, also expressing CD127 which is normally found on memory cells, and CD133, an hematopoietic stem cell marker. T(SCM) cells raised from either TIL or blood secreted numerous inflammatory mediators, but in lower amounts than those measured without TWS119. Finally, generated T(SCM) CD8(+) T cells expressed elevated Bcl-2 and no detectable caspase-3 activity, suggesting increased persistence. Our data support a role for Wnt/ß-catenin pathway in promoting the T(SCM) subset in human CD8(+) T cells from TIL and the periphery, which are relevant for ACT.
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal, Université de Montréal and Institut du Cancer de Montréal, Hôpital Notre-Dame, Montréal, Québec, Canada.
authors.forename: Marie-Andrée
authors.initials: MA
authors.lastname: Forget
authors.forename: Yannick
authors.initials: Y
authors.lastname: Huon
authors.forename: Alexandre
authors.initials: A
authors.lastname: Reuben
authors.forename: Cécile
authors.initials: C
authors.lastname: Grange
authors.forename: Moïshe
authors.initials: M
authors.lastname: Liberman
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Martin
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.forename: Nathalie
authors.initials: N
authors.lastname: Arbour
authors.forename: Réjean
authors.initials: R
authors.lastname: Lapointe
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D017209:Apoptosis / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D008213:Lymphocyte Activation; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D016207:Cytokines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D011758:Pyrroles; C547688:TWS 119; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C505407:CASP3 protein, human; D053148:Caspase 3