TY - JOUR
T1 - Stimulation of Wnt/ß-Catenin pathway in human CD8+ T lymphocytes from blood and lung tumors leads to a shared young/memory phenotype
AU - Forget, Marie Andrée
AU - Huon, Yannick
AU - Reuben, Alexandre
AU - Grange, Cécile
AU - Liberman, Moïshe
AU - Martin, Jocelyne
AU - Mes-Masson, Anne Marie
AU - Arbour, Nathalie
AU - Lapointe, Réjean
PY - 2012/7/30
Y1 - 2012/7/30
N2 - 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 (TSCM) phenotype upon TCR stimulation with Wnt/ß-catenin pathway activation. Here, we evaluated if TSCM 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. TSCM cells raised from either TIL or blood secreted numerous inflammatory mediators, but in lower amounts than those measured without TWS119. Finally, generated TSCM 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 TSCM subset in human CD8+ T cells from TIL and the periphery, which are relevant for ACT.
AB - 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 (TSCM) phenotype upon TCR stimulation with Wnt/ß-catenin pathway activation. Here, we evaluated if TSCM 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. TSCM cells raised from either TIL or blood secreted numerous inflammatory mediators, but in lower amounts than those measured without TWS119. Finally, generated TSCM 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 TSCM subset in human CD8+ T cells from TIL and the periphery, which are relevant for ACT.
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U2 - 10.1371/journal.pone.0041074
DO - 10.1371/journal.pone.0041074
M3 - Article
C2 - 22859966
AN - SCOPUS:84864431044
SN - 1932-6203
VL - 7
JO - PloS one
JF - PloS one
IS - 7
M1 - e41074
ER -