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

• Published in: Cancer immunology research 2018-08, Vol.6 (8), p.941-952
• Main Authors: Schinzari, Valeria, Timperi, Eleonora, Pecora, Giulia, Palmucci, Francesco, Gallerano, Daniela, Grimaldi, Alessio, Covino, Daniela Angela, Guglielmo, Nicola, Melandro, Fabio, Manzi, Emy, Sagnotta, Andrea, Lancellotti, Francesco, Sacco, Luca, Chirletti, Piero, Grazi, Gian Luca, Rossi, Massimo, Barnaba, Vincenzo
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; beta Catenin - metabolism; Carcinoma, Hepatocellular - immunology; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation - immunology; Colorectal Neoplasms - immunology; Female; Humans; Immunophenotyping; Liver Neoplasms - immunology; Lymphocytes, Tumor-Infiltrating - immunology; Male; Middle Aged; Wnt Signaling Pathway - immunology; Wnt3A Protein - immunology
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.CIR-17-0712

In this study, we investigated the role of the Wnt/β-catenin signaling pathway in antitumor immune responses. We report that the concentration of secreted Wnt3a was significantly higher in conditioned medium from tumor or nontumor tissues obtained from all hepatocellular carcinoma or colorectal cancer patients tested, than in serum of healthy donors or patients. In addition, both Wnt3a and β-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-γ and tumor necrosis factor-α production, as well as CD107a mobilization) despite their PD-1 expression. Wnt3a/β-catenin signaling in T naïve cells recapitulated the T-cell setting Indeed, the differentiation of cultured T naïve cells was arrested, producing cells that resembled the Eomes T-bet β-catenin T cells with moderate effector functions that infiltrated tumor and nontumor areas. Wnt3a blockade improved the capacity of T naïve cells to differentiate into effector cells However, Wnt3a blockade did not affect the function and phenotype of differentiated, partially exhausted, tumor-infiltrating T cells Taken together, our data suggest that Wnt3a blockade halts the capacity of Wnt/β-catenin signaling to inhibit the differentiation of T naïve cells, but it does not restore the dysfunction of differentiated T cells, in the tumor setting. .