Wnt3a/β-Catenin Signaling Conditions Differentiation of Partially Exhausted T-effector Cells in Human Cancers

In this study, we investigated the role of the Wnt/beta-catenin signaling pathway in antitumor immune responses. We report that the concentration of secreted Wnt3a was significantly higher in conditioned medium from tumor or non-tumor tissues obtained from all hepatocellular carcinoma or colorectal cancer patients tested, than in serum of healthy donors or patients. In addition, both Wnt3a and beta-catenin were overexpressed by tumor-infiltrating and nontumor-infiltrating CD4(+) or CD8(+) T cells. The majority of these T cells expressed a dysfunctional effector memory Eomes(+)T-bet(-) phenotype that we defined as partially exhausted, because they performed effector functions (in terms of interferon-gamma and tumor necrosis factor-alpha production, as well as CD107a mobilization) despite their PD-1 expression. Wnt3a/beta-catenin signaling in T naive cells in vitro recapitulated the T-cell setting in vivo. Indeed, the differentiation of cultured T naive cells was arrested, producing cells that resembled the Eomes(high)T-bet(low)beta-catenin(high) T cells with moderate effector functions that infiltrated tumor and non-tumor areas. Wnt3a blockade improved the capacity of T naive cells to differentiate into effector cells in vitro. However, Wnt3a blockade did not affect the function and phenotype of differentiated, partially exhausted, tumor-infiltrating T cells ex vivo. Taken together, our data suggest that Wnt3a blockade halts the capacity of Wnt/beta-catenin signaling to inhibit the differentiation of T naive cells, but it does not restore the dysfunction of differentiated T cells, in the tumor setting. (C) 2018 AACR.