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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.

Stimulation of Wnt/ß-Catenin Pathway in Human CD8+ T Lymphocytes from Blood and Lung Tumors Leads to a Shared Young/Memory Phenotype