Immunotherapy with checkpoint inhibitors has greatly prolonged the overall survival of cancer patients in melanoma and many other cancer types. However, only a subset of patients shows clinical responses from these interventions, which was predicated by the T cell-inflamed tumor microenvironment. T cell-inflamed phenotype is characterized by the infiltration of CD8+ T cells, CD8α/CD103-lineage dendritic cells (DCs), as well as high density of forkhead box P3 (FoxP3)+ regulatory T cells (Tregs) that are associated with the efficacy of immune checkpoint blockade. A number of regulators has been associated with T cell-inflammation in the tumor microenvironment, and WNT/β-catenin signaling is one of the best characterized. The tumor-intrinsic WNT/β-catenin signaling activation is frequently associated with poor spontaneous T cell infiltration across most human cancers. In this article, we review the essential roles of WNT/β-catenin signaling in the T cell-inflamed and non-T cell-inflamed tumor microenvironment, including the development and function of immune cells, activation of immune exclusion of tumor cells, and cancer immunosurveillance. We also discuss the impact of this pathway in driving the non-T cell-inflamed tumor microenvironment in other tumor types. To improve immunotherapy efficacy, we argue that targeting Wnt/β-catenin signaling should be a high priority for combinational cancer therapy to restore T cell infiltration.

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The IL-6/STAT3 signaling pathway is required for the development of psoriatic lesions, and tripartite motif-containing 27 (TRIM27) is a protein inhibitor of activated STAT3 (PIAS3)-interacting protein that could modulate IL-6-induced STAT3 activation. However, whether TRIM27 is associated with the IL-6/STAT3 signaling pathway in psoriasis remains enigmatic. TRIM27 expression and gene set enrichment analysis in patients with psoriasis were determined using bioinformatics. Human keratinocyte HaCaT cells treated with recombinant protein IL-6 (rh-IL-6) were transduced with lentivirus silencing TRIM27 and/or PIAS3 or, otherwise, transduced with lentivirus expressing TRIM27 and/or lentivirus silencing STAT3, or MG132, a proteasome-specific protease inhibitor. Cell proliferation and inflammation factor production were measured using Cell Counting Kit-8 and ELISA, respectively. TRIM27, proliferation marker protein Ki-67 (Ki67), phospho-STAT3 (p-STAT3), STAT3, and PIAS3 expressions were determined using real-time quantitative PCR, immunofluorescence staining, or Western blot analysis. Coimmunoprecipitation combined with ubiquitination analysis was performed to explore the interaction between TRIM27 and PIAS3. In the present study, TRIM27 expression was increased in psoriatic lesions, associated with the IL-6 signaling pathway, and induced by rh-IL-6 in a time-dependent manner. The increased cell proliferation, inflammation factor production, and expression of Ki67 and of p-STAT3 relative to STAT3 induced by rh-IL-6 and TRIM27 overexpression were significantly inhibited by TRIM27 silencing and STAT3 silencing, respectively. More importantly, TRIM27 interacted with PIAS3, and its overexpression promoted PIAS3 ubiquitination in HaCaT cells. PIAS3 silencing also significantly promoted TRIM27-dependent and IL6-induced STAT3 activation, cell proliferation, and inflammation factor production. In conclusion, our results highlight that TRIM27 expression is significantly increased by IL-6 and suggest a TRIM27/STAT3-dependent mechanism for regulation of inflammation and proliferation-associated development of psoriasis.