WNT Signaling in Cancer Immunosurveillance

doi:10.1016/j.tcb.2018.08.005

Trends in Cell Biology

Volume 29, Issue 1, January 2019, Pages 44-65

https://doi.org/10.1016/j.tcb.2018.08.005 Get rights and content

Highlights

Canonical WNT signaling plays a central role in embryogenesis, tissue homeostasis, and wound repair.

Deregulated WNT signaling is involved in virtually all stages of oncogenesis.

Impaired anticancer immunity as a result of aberrant WNT signaling is emerging as a key contributor to tumor progression and resistance to treatment.

Activation of canonical WNT signaling hampers T cell-mediated anticancer immune responses by multiple mechanisms including immune exclusion.

Deregulated WNT signaling has been shown to favor malignant transformation, tumor progression, and resistance to conventional cancer therapy in a variety of preclinical and clinical settings. Accumulating evidence suggests that aberrant WNT signaling may also subvert cancer immunosurveillance, hence promoting immunoevasion and resistance to multiple immunotherapeutics, including immune checkpoint blockers. Here, we discuss the molecular and cellular mechanisms through which WNT signaling influences cancer immunosurveillance and present potential therapeutic avenues to harness currently available WNT modulators for cancer immunotherapy.

Introduction

The term ‘WNT signaling’ embraces an evolutionary conserved group of signal transduction cascades that play central roles in embryogenesis, tissue homeostasis, wound repair, and malignancy [1]. WNT pathways govern molecular and cellular traits typically associated with stemness and the balance between self-renewal and lineage determination [2]. At the helm of these signaling cascades are WNTs, a panel of secreted cysteine-rich glycoproteins (19 in humans and mice) that operate as morphogens.

Reflecting its central role in the maintenance of organismal homeostasis, aberrant WNT signaling has been etiologically involved in the pathogenesis of a variety of human disorders, including (but not limited to) birth defects, autoimmune conditions, bone diseases, and cancer 3, 4. In particular, a substantial body of work has linked alterations in WNT signaling with oncogenesis, disease progression, and resistance to treatment in a variety of oncological settings 5, 6. Accumulating evidence suggests that aberrant WNT signaling activated by oncogenic mutations mediates protumoral functions not only by endowing transformed cells with malignant features but also by impairing anticancer immunosurveillance [7].

Here, we review the mechanisms whereby WNT signaling impinges on immune functions, with a special emphasis on cancer immunosurveillance, and discuss the therapeutic potential of harnessing currently available WNT modulators to implement cancer immunotherapy.

Section snippets

Molecular Regulation of Canonical WNT Signaling

Soluble WNT proteins mediate their biological effects upon binding to cognate receptors from the Frizzled (FZD) family (10 in humans and mice). Depending on multiple parameters, including (but not limited to) the precise identity of the ligand and the receptor, as well as the presence of a co-receptor, this interaction can initiate one of multiple signal transduction cascades culminating with the activation of transcriptional or post-translational cellular programs [1].

The best characterized of

WNT Signaling in Immune System Development and Function

WNT signaling plays a major role in governing cellular homeostasis, including the strict regulation of immune cell development and function. Nevertheless, in contrast to the well-established significance of the WNT pathway in hair follicle and intestinal stem cell biology [2], its contribution to the homeostasis of the pluripotent progenitor cells that are at the root of hematopoiesis, known as hematopoietic stem cells (HSCs), has long been matter of debate. For example, defects in several core

WNT Signaling in Cancer

A large body of evidence implicates deregulated WNT signaling in virtually all stages of oncogenesis, from malignant transformation to metastatic dissemination and resistance to treatment (Figure 2). Indeed, Wnt1, the gene encoding the first WNT factor identified in mammals, was cloned as an oncogene in mouse mammary cancers [56]. Furthermore, the loss of one Apc allele was found to be sufficient to drive colorectal (and mammary) carcinogenesis in rodents [57], and re-expression of APC in APC

WNT Signaling and Cancer Immunosurveillance

Depending upon context, WNT signaling has been found to either positively or negatively influence anticancer immunosurveillance by regulating multiple aspects of the tumor-immune cell interplay, including the immunogenicity of malignant cells as well as the ability of immune cells to elicit effective tumor-targeting immune responses (Figure 3).

Tumor-intrinsic WNT signaling impinges on the immunogenicity of cancer cells. Thus, some components of the WNT signal transduction cascade that are

Therapeutic Opportunities for WNT Modulation in Cancer Immunotherapy

Several agents targeting core components or regulators of WNT signaling have been developed for cancer therapy during the past few years [130]. Although none of these molecules are currently approved by regulatory agencies for use in patients, several are currently being tested in clinical trials listed in the U.S. National Library of Medicine database (https://www.clinicaltrials.gov/).

Initially, attention was mainly devoted to the disruption of WNT-driven tumor growth, leading to the

Concluding Remarks

The studies discussed in this review article point to a role for WNT signaling in tumor initiation, progression to malignancy, and resistance to therapeutics. WNT signaling can impact not only the biology of (pre)malignant cells but also the ability of cancer cells to evade the immune system. Thus, WNT modulators currently stand out as promising candidates to improve the efficacy of various immunotherapeutic agents in the context of combinatorial treatment regimens, a possibility that is

Acknowledgments

We thank Drs Yuxuan Miao, Rene Adam, and Hanseul Yang (Rockefeller University) for comments on this review article. We apologize to the many authors with articles dealing with WNT signaling and cancer immunotherapy that we were not able to discuss and cite owing to space limitations. L.G. is supported by a startup grant from the Department of Radiation Oncology at Weill Cornell Medical College (New York, USA) and by donations from Sotio a.s. (Prague, Czech Republic), Phosplatin (New York, USA),

Disclaimer Statement

L.G. provides remunerated consulting to OmniSEQ (Buffalo, NY, USA). S.S. serves on the scientific advisory board for Venn Therapeutics.

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Trends in Cell Biology

ReviewWNT Signaling in Cancer Immunosurveillance

Highlights

Introduction

Section snippets

Molecular Regulation of Canonical WNT Signaling

WNT Signaling in Immune System Development and Function

WNT Signaling in Cancer

WNT Signaling and Cancer Immunosurveillance

Therapeutic Opportunities for WNT Modulation in Cancer Immunotherapy

Concluding Remarks

Acknowledgments

Disclaimer Statement

Cell

Cell

Immunity

Cell Rep.

Cell

Cell

Cell

Blood

Blood

Cell

Cell Stem Cell

Immunity

Immunity

Immunol. Lett.

Immunity

Immunity

Immunity

Blood

Immunity

Cell Rep.

Immunity

Cell

Cancer Cell

Cancer Cell

Cancer Cell

Cell Stem Cell

Cell

Cell

Cancer Cell

Cell

Cancer Cell

Cell

Cell

Cancer Cell

Cancer Cell

Wnt some lose some: transcriptional governance of stem cells by Wnt/beta-catenin signaling

Genes Dev.

The genetics of bone mass and susceptibility to bone diseases

Nat. Rev. Rheumatol.

Planar cell polarity in development and disease

Nat. Rev. Mol. Cell Biol.

WNT signalling in prostate cancer

Nat. Rev. Urol.

Collateral damage: insights into bacterial mechanisms that predispose host cells to cancer

Nat. Rev. Microbiol.

Impact of oncogenic pathways on evasion of antitumour immune responses

Nat. Rev. Cancer

The beta-catenin destruction complex

Cold Spring Harb. Perspect. Biol.

Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation

Nat. Struct. Mol. Biol.

Tcf3: a transcriptional regulator of axis induction in the early embryo

Development

Temporal layering of signaling effectors drives chromatin remodeling during hair follicle stem cell lineage progression

Cell Stem Cell

Notum deacylates Wnt proteins to suppress signalling activity

Nature

Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling

Nature

Secreted and transmembrane wnt inhibitors and activators

Cold Spring Harb. Perspect. Biol.

Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors

Nature

ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner

Nature

Review
WNT Signaling in Cancer Immunosurveillance