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

Abstract

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 EomesT-betphenotype 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 EomesT-betβ-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. .

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

“…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.…”

“…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)…”

“…Wnt/β-catenin signaling in Tregs promotes its survival, activity and infiltration (29)(30)(31) Wnt3a/β-catenin signaling suppresses effector T cell differentiation (28,32) Wnt/β-catenin-signaling limits the expansion of tumor-antigen specific CD8 + T cells and is important in the maintenance of stemness of memory CD8 + T cells (28,32) Wnt signaling in CD4 + T cells favors Th17 cell differentiation (33,34)…”

Single cell transcriptome analysis reveals RGS1 as a new marker and promoting factor for T cell exhaustion in multiple cancers

“…In the CRC_S1 pathways, wnt signaling pathway was upregulated in our study. It has been reported that wnt signaling pathway contributes to tumor progression [83] and its blockade can improve the generation of effector cells [84] , thus the upregulation of wnt signaling pathway might contribute to T cell exhaustion and facilitate the growth of tumor; In the NSCLC_S1 pathways, the upregulated apoptosis may lead to the impaired function of T cells [85] .…”

Wnt3a promotes radioresistance via autophagy in squamous cell carcinoma of the head and neck

“…Serum Wnt3a expression levels in 108 samples from patients with SCCHN were quantified according to the manufacturer's instructions of the Human Protein Wnt3a ELISA kit (Cat. CSB‐EL026136HU, Cusabio Technology, Houston, TX, USA) …”