The Wnt/b-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/b-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 CD8þ effector memory T cells with increased expression of Tbet and IFNg and reduced expression of Tcf1. However, the effect was not attributable to the interruption of T-cell–intrinsic b-catenin signaling, because Wnt3a/b-catenin activation correlated with enhanced, not reduced, T-cell effector functions both ex vivo and in vitro. Adoptively transferred CD8þ 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/b-catenin pathway in antitumor effector T cells and suggest that Wnt3a neutralization might be a promising immunotherapy for rescuing dendritic cell activities.

Pacella I., Cammarata I., Focaccetti C., Miacci S., Gulino A., Tripodo C., et al. (2018). Wnt3a neutralization enhances T-cell responses through indirect mechanisms and restrains tumor growth. CANCER IMMUNOLOGY RESEARCH, 6(8), 953-964 [10.1158/2326-6066.CIR-17-0713].

Wnt3a neutralization enhances T-cell responses through indirect mechanisms and restrains tumor growth

Gulino A.;Tripodo C.;
2018-01-01

Abstract

The Wnt/b-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/b-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 CD8þ effector memory T cells with increased expression of Tbet and IFNg and reduced expression of Tcf1. However, the effect was not attributable to the interruption of T-cell–intrinsic b-catenin signaling, because Wnt3a/b-catenin activation correlated with enhanced, not reduced, T-cell effector functions both ex vivo and in vitro. Adoptively transferred CD8þ 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/b-catenin pathway in antitumor effector T cells and suggest that Wnt3a neutralization might be a promising immunotherapy for rescuing dendritic cell activities.
http://cancerimmunolres.aacrjournals.org/content/6/8/953.full-text.pdf
Pacella I., Cammarata I., Focaccetti C., Miacci S., Gulino A., Tripodo C., et al. (2018). Wnt3a neutralization enhances T-cell responses through indirect mechanisms and restrains tumor growth. CANCER IMMUNOLOGY RESEARCH, 6(8), 953-964 [10.1158/2326-6066.CIR-17-0713].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/395002
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