Upregulated Wnt/β-catenin signaling is associated with increased cancer cell resistance and cancer cell-elicited immunosuppression. In non-neoplastic immune cells, upregulated Wnt/β-catenin is, however, associated with either immunosuppression or immunostimulation. Therefore, it is difficult to predict the therapeutic impact inhibitors of Wnt/β-catenin signaling will have when combined with cancer immunotherapy. Here, we evaluated the benefit(s) of the Wnt/β-catenin signaling inhibitor XAV939 in the in vitro elimination of LNCaP prostate cancer cells when cocultured with lymphocytes from patients with localized biochemically recurrent prostate cancer (BRPCa). We found that 5 µM XAV939 inhibited β-catenin translocation to the nucleus in LNCaP cells and CD4+ BRPCa lymphocytes without affecting their proliferation and viability. Preconditioning BRPCa lymphocytes with 5 µM XAV939 accelerated the elimination of LNCaP cells during the coculturing. However, during subsequent re-coculturing with fresh LNCaP cells, BRPCa lymphocytes were no longer able to eliminate LNCaP cells unless coculturing and re-coculturing were performed in the presence of 5 µM XAV939. Comparable results were obtained for PC-3 prostate cancer cells. These findings provide a rationale for combining cell-based immunotherapy of PCa with inhibitors of Wnt/β-catenin signaling.

Institute of Immunology Charles University 2nd Faculty of Medicine and Motol University Hospital Prague Czech Republic

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Nusse R, Clevers H. Wnt/beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell. 2017;169(6):985–999. doi: 10.1016/j.cell.2017.05.016. PubMed DOI

Tortelote GG, Reis RR, de Almeida Mendes F, Abreu JG. Complexity of the Wnt/betacatenin pathway: Searching for an activation model. Cell Signal. 2017;40:30–43. doi: 10.1016/j.cellsig.2017.08.008. PubMed DOI

Valenta T, Hausmann G, Basler K. The many faces and functions of beta-catenin. EMBO J. 2012;31(12):2714–2736. doi: 10.1038/emboj.2012.150. PubMed DOI PMC

de Sousa EMF, Vermeulen L Wnt Signaling in Cancer Stem Cell Biology. Cancers 8 (7). 10.3390/cancers8070060 (2016). PubMed PMC

Pai SG, et al. Wnt/beta-catenin pathway: modulating anticancer immune response. Journal of hematology & oncology. 2017;10(1):101. doi: 10.1186/s13045-017-0471-6. PubMed DOI PMC

van Andel H, et al. Loss of CYLD expression unleashes Wnt signaling in multiple myeloma and is associated with aggressive disease. Oncogene. 2017;36(15):2105–2115. doi: 10.1038/onc.2016.368. PubMed DOI

Jang GB, et al. Blockade of Wnt/beta-catenin signaling suppresses breast cancer metastasis by inhibiting CSC-like phenotype. Scientific reports. 2015;5:12465. doi: 10.1038/srep12465. PubMed DOI PMC

Damsky WE, et al. beta-catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas. Cancer Cell. 2011;20(6):741–754. doi: 10.1016/j.ccr.2011.10.030. PubMed DOI PMC

Lee E, Ha S, Logan SK. Divergent Androgen Receptor and Beta-Catenin Signaling in Prostate Cancer Cells. PLoS One. 2015;10(10):e0141589. doi: 10.1371/journal.pone.0141589. PubMed DOI PMC

Sun Y, et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med. 2012;18(9):1359–1368. doi: 10.1038/nm.2890. PubMed DOI PMC

Krause M, Dubrovska A, Linge A, Baumann M. Cancer stem cells: Radioresistance, prediction of radiotherapy outcome and specific targets for combined treatments. Advanced drug delivery reviews. 2017;109:63–73. doi: 10.1016/j.addr.2016.02.002. PubMed DOI

Yaguchi T, et al. Immune suppression and resistance mediated by constitutive activation of Wnt/beta-catenin signaling in human melanoma cells. J Immunol. 2012;189(5):2110–2117. doi: 10.4049/jimmunol.1102282. PubMed DOI

Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231–235. doi: 10.1038/nature14404. PubMed DOI

Tran FH, Zheng JJ. Modulating the wnt signaling pathway with small molecules. Protein science: a publication of the Protein. Society. 2017;26(4):650–661. doi: 10.1002/pro.3122. PubMed DOI PMC

Krishnamurthy N, Kurzrock R. Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer treatment reviews. 2018;62:50–60. doi: 10.1016/j.ctrv.2017.11.002. PubMed DOI PMC

Ferri M, et al. Targeting Wnt-driven cancers: Discovery of novel tankyrase inhibitors. Eur J Med Chem. 2017;142:506–522. doi: 10.1016/j.ejmech.2017.09.030. PubMed DOI

Mariotti L, Pollock K, Guettler S. Regulation of Wnt/beta-catenin signalling by tankyrase-dependent poly(ADP-ribosyl)ation and scaffolding. Br J Pharmacol. 2017 doi: 10.1111/bph.14038. PubMed DOI PMC

Fu C, et al. beta-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10. Proc Natl Acad Sci USA. 2015;112(9):2823–2828. doi: 10.1073/pnas.1414167112. PubMed DOI PMC

Suryawanshi A, Tadagavadi RK, Swafford D, Manicassamy S. Modulation of Inflammatory Responses by Wnt/beta-Catenin Signaling in Dendritic Cells: A Novel Immunotherapy Target for Autoimmunity and Cancer. Frontiers in immunology. 2016;7:460. doi: 10.3389/fimmu.2016.00460. PubMed DOI PMC

Ganesh S, et al. beta-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models. Molecular cancer therapeutics. 2018;17(2):544–553. doi: 10.1158/1535-7163.MCT-17-0605. PubMed DOI PMC

Zhang Z, et al. Inhibition of the Wnt/beta-Catenin Pathway Overcomes Resistance to Enzalutamide in Castration-Resistant Prostate Cancer. Cancer Res. 2018;78(12):3147–3162. doi: 10.1158/0008-5472.CAN-17-3006. PubMed DOI PMC

Horoszewicz JS, et al. LNCaP model of human prostatic carcinoma. Cancer Res. 1983;43(4):1809–1818. PubMed

Kaighn ME, Narayan KS, Ohnuki Y, Lechner JF, Jones LW. Establishment and characterization of a human prostatic carcinoma cell line (PC-3) Investigative urology. 1979;17(1):16–23. PubMed

Taborska P, et al. Personalized ex vivo multiple peptide enrichment and detection of T cells reactive to multiple tumor-associated antigens in prostate cancer patients. Medical oncology. 2017;34(10):173. doi: 10.1007/s12032-017-1035-x. PubMed DOI

Turner JG, et al. XPO1 inhibitor combination therapy with bortezomib or carfilzomib induces nuclear localization of IkappaBalpha and overcomes acquired proteasome inhibitor resistance in human multiple myeloma. Oncotarget. 2016;7(48):78896–78909. doi: 10.18632/oncotarget.12969. PubMed DOI PMC

Smrz D, Iwaki S, McVicar DW, Metcalfe DD, Gilfillan AM. TLR-mediated signaling pathways circumvent the requirement for DAP12 in mast cells for the induction of inflammatory mediator release. Eur J Immunol. 2010;40(12):3557–3569. doi: 10.1002/eji.201040573. PubMed DOI PMC

Taborska P, Bartunkova J, Smrz D. Simultaneous in vitro generation of human CD34(+)-derived dendritic cells and mast cells from non-mobilized peripheral blood mononuclear cells. J Immunol Methods. 2018;458:63–73. doi: 10.1016/j.jim.2018.04.005. PubMed DOI

Li C, et al. XAV939 inhibits the proliferation and migration of lung adenocarcinoma A549 cells through the WNT pathway. Oncology letters. 2018;15(6):8973–8982. doi: 10.3892/ol.2018.8491. PubMed DOI PMC

Pan F, et al. Inhibitory effects of XAV939 on the proliferation of small-cell lung cancer H446 cells and Wnt/beta-catenin signaling pathway in vitro. Oncology letters. 2018;16(2):1953–1958. doi: 10.3892/ol.2018.8790. PubMed DOI PMC

Guo W, Shen F, Xiao W, Chen J, Pan F Wnt inhibitor XAV939 suppresses the viability of small cell lung cancer NCI-H446 cells and induces apoptosis. Oncology letters14(6), 6585–6591, 10.3892/ol.2017.7100OL-0-0-7100. PubMed PMC

Togashi Y, et al. Inhibition of beta-Catenin enhances the anticancer effect of irreversible EGFR-TKI in EGFR-mutated non-small-cell lung cancer with a T790M mutation. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 2015;10(1):93–101. doi: 10.1097/JTO.0000000000000353. PubMed DOI

Gattinoni L, Ji Y, Restifo NP. Wnt/beta-catenin signaling in T-cell immunity and cancer immunotherapy. Clin Cancer Res. 2010;16(19):4695–4701. doi: 10.1158/1078-0432.CCR-10-0356. PubMed DOI PMC

Huang SM, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature. 2009;461(7264):614–620. doi: 10.1038/nature08356. PubMed DOI

Emons G, et al. Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/beta-catenin Signaling. Mol Cancer Res. 2017;15(11):1481–1490. doi: 10.1158/1541-7786.MCR-17-0205. PubMed DOI PMC

Zhang Q, et al. Enhancement of Radiation Sensitivity in Lung Cancer Cells by a Novel Small Molecule Inhibitor That Targets the beta-Catenin/Tcf4 Interaction. PLoS One. 2016;11(3):e0152407. doi: 10.1371/journal.pone.0152407. PubMed DOI PMC

Rajan P, et al. Next-generation sequencing of advanced prostate cancer treated with androgen-deprivation therapy. European urology. 2014;66(1):32–39. doi: 10.1016/j.eururo.2013.08.011. PubMed DOI PMC

Cojoc M, et al. Aldehyde Dehydrogenase Is Regulated by beta-Catenin/TCF and Promotes Radioresistance in Prostate Cancer Progenitor Cells. Cancer Res. 2015;75(7):1482–1494. doi: 10.1158/0008-5472.CAN-14-1924. PubMed DOI

Sultan M, et al. Hide-and-seek: the interplay between cancer stem cells and the immune system. Carcinogenesis. 2017;38(2):107–118. doi: 10.1093/carcin/bgw115. PubMed DOI

Ding Y, Shen S, Lino AC, Curotto de Lafaille MA, Lafaille JJ. Beta-catenin stabilization extends regulatory T cell survival and induces anergy in nonregulatory T cells. Nat Med. 2008;14(2):162–169. doi: 10.1038/nm1707. PubMed DOI

Dai W, et al. Blockade of Wnt/beta-Catenin Pathway Aggravated Silica-Induced Lung Inflammation through Tregs Regulation on Th Immune Responses. Mediators of inflammation. 2016;2016:6235614. doi: 10.1155/2016/6235614. PubMed DOI PMC

Driessens G, et al. Beta-catenin inhibits T cell activation by selective interference with linker for activation of T cells-phospholipase C-gamma1 phosphorylation. J Immunol. 2011;186(2):784–790. doi: 10.4049/jimmunol.1001562. PubMed DOI PMC

Manicassamy S, et al. Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science. 2010;329(5993):849–853. doi: 10.1126/science.1188510. PubMed DOI PMC

Lu W, et al. Suppression of Wnt/beta-catenin signaling inhibits prostate cancer cell proliferation. European journal of pharmacology. 2009;602(1):8–14. doi: 10.1016/j.ejphar.2008.10.053. PubMed DOI PMC

Patel A, Fong L. Immunotherapy for Prostate Cancer: Where Do We Go From Here?-PART 1: Prostate Cancer Vaccines. Oncology. 2018;32(3):112–120. PubMed

Patel A, Fong L. Immunotherapy for Prostate Cancer: Where Do We Go From Here?-PART 2: Checkpoint Inhibitors, Immunotherapy Combinations, Tumor Microenvironment Modulation, and Cellular Therapies. Oncology. 2018;32(6):e65–e73. PubMed

Fong L, et al Activated lymphocyte recruitment into the tumor microenvironment following preoperative sipuleucel-T for localized prostate cancer. Journal of the National Cancer Institute 106(11), 10.1093/jnci/dju268 (2014). PubMed PMC

Vuky J, et al. Phase II trial of neoadjuvant docetaxel and CG1940/CG8711 followed by radical prostatectomy in patients with high-risk clinically localized prostate cancer. The oncologist. 2013;18(6):687–688. doi: 10.1634/theoncologist.2011-0234. PubMed DOI PMC

Fucikova J, et al. Phase I/II trial of dendritic cell-based active cellular immunotherapy with DCVAC/PCa in patients with rising PSA after primary prostatectomy or salvage radiotherapy for the treatment of prostate cancer. Cancer immunology, immunotherapy: CII. 2018;67(1):89–100. doi: 10.1007/s00262-017-2068-x. PubMed DOI PMC

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