Trends in Pharmacological Sciences
ReviewTargeting Wnt/β-Catenin Signaling for Cancer Immunotherapy
Section snippets
Cancer Immunotherapy and Wnt/β-Catenin Signaling
Cancer immunotherapy is revolutionizing the treatment of cancer by activating or reactivating the tumor-immunity cycle [1]. Under normal circumstances, antigens released from cancer cells are firstly encountered by dendritic cells (DCs), before priming and activating T cells (CD4+ or CD8+ T cells). Trafficking and infiltration of T cells into tumor sites leads to cancer cell elimination and antigen release [2]. Such a cyclic process is supposed to be self-propagating in order to eventually kill
Wnt/β-Catenin Signaling and Dendritic Cells
In the tumor-immune cycle, the first steps are taken by DCs that present tumor antigens on major histocompatibility complex molecules and prime effector T cells. Expression of cytokines (e.g., IL-12, TGFβ, IL-6) and chemokines (e.g., CXCL13, CXCL9/10) in DCs enhances the immune response 21, 22. Failure of this initiation of the tumor-immune cycle is often caused by absence of tumor neoantigens, deficiency of antigen presentation, or transformation of DCs into a regulatory state [7].
It has been
Wnt/β-Catenin Signaling and CD8+ T Cells
The key effectors in the tumor-immune cycle are T cells expressing cell surface glycoprotein CD8 (CD8+ T cells). In the tumor-immune system, DCs and co-stimulatory molecules activate and prime CD8+ T cells, which in turn travel and infiltrate into tumor sites to kill target cancer cells [31]. During tumor progression, tumor cells escape from immune elimination by preventing CD8+ T cell infiltration, excluding or inactivating CD8+ T cells [7].
Upon stimulation by APCs, mature naïve CD8+ T cells
Wnt/β-Catenin Signaling and T Helper Cells
T helper (Th) cells are characterized by the expression of surface protein CD4. The major role of Th cells in helping the CD8+ T cell antitumor response is through the release of T cell cytokines [41]. Th cells are usually divided into Th1, Th2, and Th17, based on their cytokine secretion and function [42]. IFN-γ produced by Th1 cells enhances tumor-antigen recognition and CD8+ T cell infiltration [41]. Th cells also directly inhibit tumor cells or enhance antitumor immunity through
Wnt/β-Catenin Signaling and Regulatory T Cells
Regulatory T (Treg) cells belong to the CD4+CD25+Foxp3+ T cell lineage that are essential for maintenance of immunosuppression and tolerance to immune attack by inhibiting the effector T cell response 53, 54. The development and function of Treg cells is regulated by key transcription factors, including forkhead box P3 (FOXP3) [55]. Infiltration of Treg cells into tumors is believed to result in suppression of the antitumor immune response [7].
Wnt/β-catenin signaling is critical for the
Wnt/β-Catenin Signaling and Tumor Cells
The last step in the tumor-immune cycle is that tumor cells are recognized and killed by effector T cells (Figure 1). The most common strategies used by tumor cells to escape immune attack are expression of negative regulatory molecules PD-1/L1 and generation of mutant tumor antigens by immunoediting 65, 66.
To avoid and generate resistance to immune attack, tumor cells express innate immune regulator CD47 and adaptive immune checkpoint PD-L1. Notably, the expression of both CD47 and PD-L1 has
Targeting Wnt/β-Catenin Signaling to Enhance Cancer Immunotherapy
According to the hallmarks of cancer defined by Hanahan and Weinberg, mutation of cancer driver genes and deregulation of the immune system are required for tumor initiation and progression [3]. Compared with conventional chemotherapy, molecular targeted therapy that blocks cancer driver genes greatly benefits patients, with fewer side-effects [71]; however, the median prolonged survival time is only a few months and tumor relapse inevitably occurs. For cancer immunotherapy, although a dramatic
Concluding Remarks
In this review article, we have comprehensively reviewed the correlation between Wnt/β-catenin signaling and the tumor-immune system, with particular emphasis on T cells. Specifically, abnormal regulation of a number of Wnt direct target genes in immune cells and tumor cells has been demonstrated to be responsible for the failure of cancer immunotherapy. By dissecting the underlying mechanisms, we have argued that targeting Wnt/β-catenin signaling is potentially able to overcome all the
Acknowledgements
The work was supported by the Shanghai Pujiang Program (17PJ1408700) and the National Natural Science Foundation of China (NSFC) (81703757).
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