Wnt3a/b-Catenin signaling conditions differentiation of partially exhausted T-effector cells in human cancers

Valeria Schinzari, Eleonora Timperi, Giulia Pecora, Francesco Palmucci, Daniela Gallerano, Alessio Grimaldi, Daniela Angela Covino, Nicola Guglielmo, Fabio Melandro, Emy Manzi, Andrea Sagnotta, Francesco Lancellotti, Luca Sacco, Piero Chirletti, Gian Luca Grazi, Massimo Rossi, Vincenzo Barnaba

Research output: Contribution to journalArticle

Abstract

In this study, we investigated the role of the Wnt/b-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 b-catenin were overexpressed by tumor-infiltrating and nontumor-infiltrating CD4þ or CD8þ T cells. The majority of these T cells expressed a dysfunctional effector memory EomesþT-betphenotype that we defined as partially exhausted, because they performed effector functions (in terms of interferon-g and tumor necrosis factor-a production, as well as CD107a mobilization) despite their PD-1 expression. Wnt3a/b-catenin signaling in T naïve cells in vitro recapitulated the T-cell setting in vivo. Indeed, the differentiation of cultured T naïve cells was arrested, producing cells that resembled the EomeshighT-betlowb-cateninhigh 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 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/b-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.

Original languageEnglish
Pages (from-to)941-952
Number of pages12
JournalCancer immunology research
Volume6
Issue number8
DOIs
Publication statusPublished - Aug 1 2018

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Fingerprint Dive into the research topics of 'Wnt3a/b-Catenin signaling conditions differentiation of partially exhausted T-effector cells in human cancers'. Together they form a unique fingerprint.

  • Cite this

    Schinzari, V., Timperi, E., Pecora, G., Palmucci, F., Gallerano, D., Grimaldi, A., Covino, D. A., Guglielmo, N., Melandro, F., Manzi, E., Sagnotta, A., Lancellotti, F., Sacco, L., Chirletti, P., Grazi, G. L., Rossi, M., & Barnaba, V. (2018). Wnt3a/b-Catenin signaling conditions differentiation of partially exhausted T-effector cells in human cancers. Cancer immunology research, 6(8), 941-952. https://doi.org/10.1158/2326-6066.CIR-17-0712