Review
Targeting Wnt/β-Catenin Signaling for Cancer Immunotherapy

https://doi.org/10.1016/j.tips.2018.03.008Get rights and content

Highlights

Despite some success with checkpoint inhibitors in cancer patients, cancer immunotherapy has met challenges regarding the low response rates in major cancer patients and tumor relapse after initial response.

As a well-known therapeutic target of cancer, Wnt/β-catenin signaling is focused mainly on tumor cells. Increasing evidence highlights the essential role of Wnt/β-catenin signaling in the cancer immunity system.

By directly controlling the expression of critical regulators of dendritic cells, effector T cells, regulatory T cells, T helper cells, and tumor cells, abnormal activation of Wnt/β-catenin signaling disrupts the tumor-immune cycle and facilitates cancer development.

Combination therapy with modulation of Wnt/β-catenin signaling is expected to overcome the primary, adaptive, and acquired resistance to cancer immunotherapy.

Despite the dramatic antitumor efficiency of certain immune checkpoint inhibitors, immunotherapy has met a bottleneck regarding the response rate and resistance in cancer patients. Increasing evidence indicates that Wnt/β-catenin signaling, one of the best-characterized cancer drivers, promotes cancer progression by regulating the tumor-immune cycle in most of the nodes, including dendritic cells, T cells, and tumor cells. Specifically, abnormal Wnt/β-catenin signaling directly alters a number of regulators critical for the antitumor activities of T cells, especially effector T cells, T helper cells, and regulatory T cells. We propose that targeting Wnt/β-catenin signaling would potentially improve clinical outcomes of cancer patients by overcoming the primary, adaptive, and acquired resistance to 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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