Following the observation that Wnt3a in MC38 tumors was primarily produced by stromal cells, Pacella et al. examined the effects of neutralization of Wnt3a on T cell effector functions. Administration of Wnt3a-neutralizing antibody in tumor-bearing mice reduced MC38 tumor growth and led to preferential expansion of tumor antigen-specific CD8+ effector memory T cells with increased expression of Tbet and IFNγ, and decreased expression of Tcf1. The effect was not the result of the hypothesized interruption of B-catenin signaling in CD8+ T cells but rather the result of restored dendritic cell maturation and activity following Wnt3a neutralization.

The Wnt/beta-catenin pathway regulates T-cell functions, including the repression of effector functions to the advantage of memory development via Tcf1. In a companion study, we demonstrate that, in human cancers, Wnt3a/beta-catenin signaling maintains tumor-infiltrating T cells in a partially exhausted status. Here, we have investigated the effects of Wnt3a neutralization in vivo in a mouse tumor model. Abundant Wnt3a was released, mostly by stromal cells, in the tumor microenvironment. We tested whether Wnt3a neutralization in vivo could rescue the effector capacity of tumor-infiltrating T cells, by administering an antibody to Wnt3a to tumor-bearing mice. This therapy restrained tumor growth and favored the expansion of tumor antigen-specific CD8(+) effector memory T cells with increased expression of Tbet and IFNgamma and reduced expression of Tcf1. However, the effect was not attributable to the interruption of T-cell-intrinsic beta-catenin signaling, because Wnt3a/beta-catenin activation correlated with enhanced, not reduced, T-cell effector functions both ex vivo and in vitro Adoptively transferred CD8(+) T cells, not directly exposed to the anti-Wnt3a antibody but infiltrating previously Wnt3a-neutralized tumors, also showed improved functions. The rescue of T-cell response was thus secondary to T-cell-extrinsic changes that likely involved dendritic cells. Indeed, tumor-derived Wnt3a strongly suppressed dendritic cell maturation in vitro, and anti-Wnt3a treatment rescued dendritic cell activities in vivo Our results clarify the function of the Wnt3a/beta-catenin pathway in antitumor effector T cells and suggest that Wnt3a neutralization might be a promising immunotherapy for rescuing dendritic cell activities. Cancer Immunol Res; 6(8); 1-12. (c)2018 AACR.

Author Info: (1) Dipartimento di Medicina Interna e Specialita Mediche, "Sapienza" Universita di Roma, Rome, Italy. (2) Dipartimento di Medicina Interna e Specialita Mediche, "Sapienza" Universita di

Author Info: (1) Dipartimento di Medicina Interna e Specialita Mediche, "Sapienza" Universita di Roma, Rome, Italy. (2) Dipartimento di Medicina Interna e Specialita Mediche, "Sapienza" Universita di Roma, Rome, Italy. (3) Dipartimento di Medicina Interna e Specialita Mediche, "Sapienza" Universita di Roma, Rome, Italy. (4) Dipartimento di Medicina Interna e Specialita Mediche, "Sapienza" Universita di Roma, Rome, Italy. (5) Tumor Immunology Unit, Department of Health Science, University of Palermo School of Medicine, Palermo, Italy. (6) Tumor Immunology Unit, Department of Health Science, University of Palermo School of Medicine, Palermo, Italy. (7) Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. (8) Dipartimento di Medicina Interna e Specialita Mediche, "Sapienza" Universita di Roma, Rome, Italy. vincenzo.barnaba@uniroma1.it. Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Rome, Italy. Center for Life Nano Science, Istituto Italiano di Tecnologia, Rome, Italy. (9) Dipartimento di Medicina Interna e Specialita Mediche, "Sapienza" Universita di Roma, Rome, Italy. Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Rome, Italy.

Less