Wnt3a Neutralization Enhances T-cell Responses through Indirect Mechanisms and Restrains Tumor Growth

Abstract

The Wnt/β-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/β-catenin signaling maintains tumor-infiltrating T cells in a partially exhausted status. Here, we have investigated the effects of Wnt3a neutralization in a mouse tumor model. Abundant Wnt3a was released, mostly by stromal cells, in the tumor microenvironment. We tested whether Wnt3a neutralization 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 IFNγ and reduced expression of Tcf1. However, the effect was not attributable to the interruption of T-cell-intrinsic β-catenin signaling, because Wnt3a/β-catenin activation correlated with enhanced, not reduced, T-cell effector functions both and 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 , and anti-Wnt3a treatment rescued dendritic cell activities Our results clarify the function of the Wnt3a/β-catenin pathway in antitumor effector T cells and suggest that Wnt3a neutralization might be a promising immunotherapy for rescuing dendritic cell activities. .

Wnt Signaling Cascade in Dendritic Cells and Regulation of Anti-tumor Immunity

“…Likewise, T cellinfiltrating human hepatocellular carcinoma and colorectal cancer are dysfunctional and show an exhausted effector memory phenotype (43,44,60). In line with these observations, Wnt3a neutralization in tumor-bearing mice controls tumor growth by augmenting the expansion of tumor-antigen-specific CD8 + T cells with enhanced effector functions (27). Furthermore, the induction of Wnt signaling is critical for maintaining stemness of memory CD8 + T cells and Treg-intrinsic β-catenin signaling is critical for Treg survival, migration and suppressive functions (29)(30)(31).…”

“…Similar observations were made upon pharmacologically blocking canonical Wnt signaling in tumor DCs (17, 23-25, 27, 48, 59). In contrast, Wnt-conditioned DCs or tumor DCs expressing a constitutively active form of β-catenin is less potent in capturing and cross-presenting TAAs (17,21,22,27,48). Collectively, these studies show that the activation of canonical Wnt signaling pathway in tumor DCs suppresses efficient capture of tumor-associated antigens and cross-priming of CD8 + T cells.…”

“…Tumor growth, migration, and metastasis (43)(44)(45) Immune cell exclusion (17,27,28,(46)(47)(48) augmented DCs activation with an increased expression of costimulatory molecules and decreased expression of co-inhibitory molecules (21,22,56). Collectively, these studies show that Wnt/β-catenin signaling interferes with DC maturation and activation in the TME.…”

“…However, the impact on anti-tumor immunity was not assessed in this study (81). In another critical study, it was shown that administration of Wnt3a-neutralizing antibodies in tumor bearing mice restrains tumor growth by potently activating DCs and boosting the expansion of tumor-specific CD8 + T cells with improved effector activities (27). Likewise, neutralizing or silencing Wnt1 in lung adenocarcinoma model augmented DC activation, resulting in increased recruitment and accumulation of CTLs in the TME (17).…”

“…Tumor DCs-deficient in LRP5/6 or β-catenin is more potent in capturing and cross-presenting TAAs to CD8 + T cells (21)(22)(23)(24) Tumor DCs lacking LRP5/6 or β-catenin are programmed to induce Th1/Th17 cells (21,22) Active Wnt/β-catenin signaling affects trafficking of DCs to tumors and TDLNs (17) Active Wnt/β-catenin signaling in tumor DCs regulates metabolic pathways involving FAO, vitamin A, and tryptophan to induce regulatory T cell (Treg) response (21)(22)(23)(24)(25)(26) Wnt-signaling in tumor DCs suppresses chemokines that are critical of recruitment and accumulation of CTL in the TME (17,27,28)…”