肿瘤免疫中Wnt/β‑catenin信号通路的研究进展

摘要/Abstract

摘要：

Wnt/β?catenin信号通路是一条高度保守的通路，可以起到调节细胞的增殖、分化、凋亡，干细胞的自我更新，组织稳态和创伤愈合的作用。几乎所有肿瘤的发生发展均与Wnt通路的失调有关。Wnt/β?catenin信号转导的异常激活，可以通过对免疫细胞的直接或间接作用，促进免疫排斥，进而阻碍T细胞介导的抗肿瘤免疫反应。本文对Wnt/β?catenin信号影响肿瘤进展和免疫监视的过程，以及靶向该信号通路治疗癌症的策略作一综述。

关键词:Wnt/β?catenin信号通路,肿瘤免疫,靶向治疗

Abstract:

The Wnt/β-catenin signaling pathway is a highly conserved pathway that regulates cell proliferation， differentiation， apoptosis， stem cell self-renewal， tissue homeostasis， and wound healing. Dysregulation of the Wnt pathway is involved in almost all stages of tumorigenesis in various cancers.Abnormal activation of Wnt/β-catenin signal transduction contributes to immune rejection and inhibits T cell-mediated antitumor immune responses through direct or indirect effects on immune cells. In this review， we summarize the processes by which Wnt/β-catenin signaling influences tumor progression and immune surveillance， as well as strategies for targeting this signaling pathway at different levels for cancer therapy.

Key words:Wnt/β-catenin signaling pathway,tumor immunity,targeted therapy

张欢欢, 张蕾, 崔洁, 梁尹攀, 伊淑莹. 肿瘤免疫中Wnt/β‑catenin信号通路的研究进展[J]. betway必威登陆网址（betway.com ）学报, 2023, 44(9): 716-720.

Huanhuan ZHANG, Lei ZHANG, Jie CUI, Yinpan LIANG, Shuying YI. Research progress of Wnt/β-catenin signaling pathway in tumor immunity[J]. Journal of Shandong First Medical Unversity & Shandong Academy of Medical Sciences, 2023, 44(9): 716-720.

参考文献43

1	Chun SK， Fortin BM， Fellows RC， et al. Disruption of the circadian clock drivesApcloss of heterozygosity to accelerate colorectal cancer［J］. Sci Adv， 2022， 8（32）： eabo2389.
2	Liu J， Xiao Q， Xiao J， et al. Wnt/β-catenin signalling： function， biological mechanisms， and therapeutic opportunities［J］. Signal Transduct Target Ther， 2022， 7（1）： 3.
3	Du W， Menjivar RE， Donahue KL， et al. WNT signaling in the tumor microenvironment promotes immunosuppression in murine pancreatic cancer［J］. J Exp Med， 2023， 220（1）： e20220503.
4	Xue C， Li G， Zheng Q， et al. The functional roles of the circRNA/Wnt axis in cancer［J］. Mol Cancer， 2022， 21（1）： 108.
5	Nozais M， Loosveld M， Pankaew S， et al. MYC deficiency impairs the development of effector/memory T lymphocytes［J］. iScience， 2021， 24（7）： 102761.
6	Castagnoli L， Cancila V， Cordoba-Romero SL， et al. WNT signaling modulates PD-L1 expression in the stem cell compartment of triple-negative breast cancer［J］. Oncogene， 2019， 38（21）： 4047.
7	Pashirzad M， Johnston TP， Sahebkar A. Therapeutic effects of polyphenols on the treatment of colorectal cancer by regulating Wntβ-catenin signaling pathway［J］. J Oncol， 2021， 2021： 3619510.
8	Mammadli M， Harris R， Mahmudlu S， et al. Human Wnt/β-catenin regulates alloimmune signaling during allogeneic transplantation［J］. Cancers （Basel）， 2021， 13（15）： 3798.
9	Kim C， Jin J， Weyand CM， et al. The transcription factor TCF1 in T cell differentiation and aging［J］. Int J Mol Sci， 2020， 21（18）： 6497.
10	Imai N， Tawara I， Yamane M， et al. CD4⁺T cells support polyfunctionality of cytotoxic CD8⁺T cells with memory potential in immunological control of tumor［J］. Cancer Sci， 2020， 111（6）： 1958.
11	Sun X， Liu S， Wang D， et al. Colorectal cancer cells suppress CD4⁺T cells immunity through canonical Wnt signaling［J］. Oncotarget， 2017， 8（9）： 15168.
12	Wang B， Tian T， Kalland KH， et al. Targeting Wnt/β-catenin signaling for cancer immunotherapy［J］. Trends Pharmacol Sci， 2018， 39（7）： 648.
13	DiToro D， Harbour SN， Bando JK， et al. Insulin-like growth factors are key regulators of T helper 17 regulatory T cell balance in autoimmunity［J］. Immunity， 2020， 52（4）： 650.
14	Lengfeld JE， Lutz SE， Smith JR， et al. Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis［J］. Proc Natl Acad Sci U S A， 2017， 114（7）： E1168.
15	Togashi Y， Shitara K， Nishikawa H. Regulatory T cells in cancer immunosuppression-implications for anticancer therapy［J］. Nat Rev Clin Oncol， 2019， 16（6）： 356.
16	Quandt J， Arnovitz S， Haghi L， et al. Wnt-β-catenin activation epigenetically reprograms T_regcells in inflammatory bowel disease and dysplastic progression［J］. Nat Immunol， 2021， 22（4）： 471.
17	Dai W， Liu F， Li C， et al. Blockade of Wnt/β-Catenin Pathway Aggravated Silica-Induced Lung Inflammation through Tregs Regulation on Th Immune Responses［J］. Mediators Inflamm. 2016；2016：6235614.
18	Osman A， Yan B， Li Y， et al. TCF-1 controls T_regcell functions that regulate inflammation， CD8⁺T cell cytotoxicity and severity of colon cancer［J］. Nat Immunol， 2021， 22（9）： 1152.
19	Feng M， Jin JQ， Xia L， et al. Pharmacological inhibition of β-catenin/BCL9 interaction overcomes resistance to immune checkpoint blockades by modulating T_regcells［J］. Sci Adv， 2019， 5（5）： eaau5240.
20	Tanton H， Sewastianik T， Seo HS， et al. A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer［J］. Sci Adv， 2022， 8（17）： eabm3108.
21	Shimasaki N， Jain A， Campana D. NK cells for cancer immunotherapy［J］. Nat Rev Drug Discov， 2020， 19（3）： 200.
22	Kim SR， Won HS， Yang JH， et al. Prognostic value of Dickkopf-1 and β-catenin expression according to the antitumor immunity of CD8-positive tumor-infiltrating lymphocytes in biliary tract cancer［J］. Sci Rep， 2022， 12（1）： 1931.
23	Betella I， Turbitt WJ， Szul T， et al. Wnt signaling modulator DKK1 as an immunotherapeutic target in ovarian cancer［J］. Gynecol Oncol， 2020， 157（3）： 765.
24	Tang Y， Xu Q， Hu L， et al. Tumor microenvironment-derived R-spondins enhance antitumor immunity to suppress tumor growth and sensitize for immune checkpoint blockade therapy［J］. Cancer Discov， 2021， 11（12）： 3142.
25	Cohen SB， Smith NL， McDougal C， et al. β-catenin signaling drives differentiation and proinflammatory function of IRF8-dependent dendritic cells［J］. J Immunol， 2015， 194（1）： 210.
26	Zhao F， Xiao C， Evans KS， et al. Paracrine Wnt5a-β-catenin signaling triggers a metabolic program that drives dendritic cell tolerization［J］. Immunity， 2018， 48（1）： 147.
27	Fu C， Liang X， Cui W， et al. β-catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8⁺T cells through regulation of IL-10［J］. Proc Natl Acad Sci U S A， 2015， 112（9）： 2823.
28	Hong Y， Manoharan I， Suryawanshi A， et al. Deletion of LRP5 and LRP6 in dendritic cells enhances antitumor immunity［J］. Oncoimmunology， 2016， 5（4）： e1115941.
29	Hong Y， Manoharan I， Suryawanshi A， et al. β-catenin promotes regulatory t-cell responses in tumors by inducing vitamin a metabolism in dendritic cells［J］. Cancer Res， 2015， 75（4）： 656.
30	Macias-Ceja DC， Coll S， Bauset C， et al. IFNγ-treated macrophages induce EMT through the WNT pathway： relevance in Crohn's disease［J］. Biomedicines， 2022， 10（5）： 1093.
31	Tu T， Alba MM， Datta AA， et al. Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis［J］. Front Oncol， 2022， 12： 958696.
32	Wang Y， Zheng L， Shang W， et al. Wnt/beta-catenin signaling confers ferroptosis resistance by targeting GPX4 in gastric cancer［J］. Cell Death Differ， 2022， 29（11）： 2190.
33	Casey SC， Tong L， Li Y， et al. MYC regulates the antitumor immune response through CD47 and PD-L1［J］. Science， 2016， 352（6282）： 227.
34	He Y， Jiang X， Duan L， et al. LncRNA PKMYT1AR promotes cancer stem cell maintenance in non-small cell lung cancer via activating Wnt signaling pathway［J］. Mol Cancer， 2021， 20（1）： 156.
35	Takeuchi Y， Tanegashima T， Sato E， et al. Highly immunogenic cancer cells require activation of the WNT pathway for immunological escape［J］. Sci Immunol， 2021， 6（65）： eabc6424.
36	Pacella I， Cammarata I， Focaccetti C， et al. Wnt3a neutralization enhances T-cell responses through indirect mechanisms and restrains tumor growth［J］. Cancer Immunol Res， 2018， 6（8）： 953.
37	Kerdidani D， Chouvardas P， Arjo AR， et al. Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma［J］. Nat Commun， 2019， 10（1）： 1405.
38	Shah K， Panchal S， Patel B. Porcupine inhibitors： novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway［J］. Pharmacol Res， 2021， 167： 105532.
39	Li X， Xiang Y， Li F. et al WNT/β-catenin signaling pathway regulating T cell-inflammation in the tumor microenvironment［J］. Front Immunol， 2019， 10： 2293.
40	Phillips C， Bhamra I， Eagle C， et al. The Wnt Pathway Inhibitor RXC004 Blocks Tumor Growth and Reverses Immune Evasion in Wnt Ligand-dependent Cancer Models. Cancer Res Commun. 2022；2（9）：914-928
41	Haseeb M， Pirzada RH， Ain QU， et al. Wnt signaling in the regulation of immune cell and cancer therapeutics［J］. Cells， 2019， 8（11）： 1380.
42	López González M， Oosterhoff D， Lindenberg JJ， et al. Constitutively active GSK3β as a means to bolster dendritic cell functionality in the face of tumour-mediated immune suppression［J］. Oncoimmunology， 2019， 8（10）： e1631119.
43	Yan R， Zhu H， Huang P， et al. Liquidambaric acid inhibits Wnt/β-catenin signaling and colon cancer via targeting TNF receptor-associated factor 2［J］. Cell Rep， 2022， 38（5）： 110319.

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