Memory stem T cells generated by Wnt signaling from blood of human renal clear cell carcinoma patients

OBJECTIVE: Memory stem T cells (Tscm) have attracted attention because of their enhanced self-renewal, multipotent capacity, and anti-tumor capacities. However, little is known about Tscm in patients with renal clear cell carcinoma (RCC) and the role of Wnt signaling in these cells. We evaluated Tscm from RCC patients concerning their activation of Wnt signaling in vitro and explored the mechanism of preferential survival. METHODS: Flow cytometry identified surface markers and cytokines produced from accumulated Tscm in the presence of the glycogen synthase kinase beta inhibitor TWS119. Apoptosis was evaluated after induction using tumor necrosis factor-alpha. Immunofluorescence and Western blot analyses were used to investigate the activation of the nuclear factor-kappa B (NF-КB) pathway. RESULTS: RCC patients had a similar percentage of CD4(+) and CD8(+) Tscm as healthy donors. Activation of Wnt signaling by TWS119 resulted in the accumulation of Tscm in activated T cells, but reversal of differentiated T cells to Tscm was not achieved. Preferential survival of Tscm was associated with increased anti-apoptotic ability mediated downstream of the NF-КB activation pathway. CONCLUSIONS: The finding that Tscm can accumulate by Wnt signaling in vitro in blood from RCC patients will help in devising new cancer therapy strategies of Tscm-based adoptive immunotherapy, such as dendritic cell-stimulated Tscm, and T cell receptor or chimeric antigen receptor-engineered Tscm.