BACKGROUND: Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. However, the molecular programs mediated by IL6ST/STAT3 in prostate cancer are poorly understood. METHODS: To investigate the role of IL6ST signaling, we constitutively activated IL6ST signaling in the prostate epithelium of a Pten-deficient prostate cancer mouse model in vivo and examined IL6ST expression in large cohorts of prostate cancer patients. We complemented these data with in-depth transcriptomic and multiplex histopathological analyses. RESULTS: Genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high IL6ST mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor. CONCLUSIONS: Our findings demonstrate a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development by inducing senescence and immune cell attraction. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as a functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy.

Biochemical Institute University of Kiel Kiel Germany

BioTechMed Graz Graz Austria

Center for Biomarker Research in Medicine GmbH Graz Styria Austria

Center for Cancer Research Medical University of Vienna and Comprehensive Cancer Center Vienna Austria

Central European Institute of Technology Masaryk University Brno Czech Republic

Christian Doppler Laboratory for Applied Metabolomics Medical University of Vienna Vienna Austria

Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Biological Sciences and Pathobiology Physiology and Biophysics University of Veterinary Medicine Vienna Vienna Austria

Department of Biomedical Imaging and Image Guided Therapy Division of Nuclear Medicine Medical University of Vienna Vienna Austria

Department of Biomedical Sciences Malmö Universitet Malmö Sweden

Department of Cell Biology Charles University Prague Czech Republic and Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University Vestec u Prahy Czech Republic

Department of Dermatology and Venereology Medical University of Graz Graz Austria

Department of Molecular Biology Umeå University Umeå Sweden

Department of Nutritional Sciences Faculty of Life Sciences University of Vienna Vienna Austria

Department of Pathology Medical University of Vienna Vienna Austria

Institute of Animal Breeding and Genetics University of Veterinary Medicine Vienna Vienna Austria

Institute of Medical Biochemistry University of Veterinary Medicine Vienna Vienna Austria

Unit of Laboratory Animal Pathology University of Veterinary Medicine Vienna Vienna Austria

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Wang L, Lu B, He M, Wang Y, Wang Z, Du L. Prostate Cancer Incidence and Mortality: Global Status and Temporal Trends in 89 Countries From 2000 to 2019. Front Public Health. 2022;10:176. PubMed PMC

del Pino-Sedeño T, Infante-Ventura D, de Armas CA, de Pablos-Rodríguez P, Rueda-Domínguez A, Serrano-Aguilar P, Trujillo-Martín MM. Molecular Biomarkers for the Detection of Clinically Significant Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol Open Sci. 2022;46:105–27. PubMed PMC

Scherger AK, Al-Maarri M, Maurer HC, et al. Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma. JCI Insight. 2019;4:e128435–e128435. PubMed PMC

Golus M, Bugajski P, Chorbińska J, Krajewski W, Lemiński A, Saczko J, Kulbacka J, Szydełko T, Małkiewicz B. STAT3 and Its Pathways’ Dysregulation-Underestimated Role in Urological Tumors. Cells. 2022;11:3024. PubMed PMC

Mora LB, Buettner R, Seigne J, et al. Constitutive activation of Stat3 in human prostate tumors and cell lines: Direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Res. 2002;62:6659–66. PubMed

Lee H, Jeong AJ, Ye SK. Highlighted STAT3 as a potential drug target for cancer therapy. BMB Rep. 2019;52:415–23. PubMed PMC

Pencik J, Philippe C, Schlederer M, et al. STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway. Mol Cancer. 2023;22:133. PubMed PMC

Pencik J, Schlederer M, Gruber W, et al. STAT3 regulated ARF expression suppresses prostate cancer metastasis. Nat Commun. 2015;6:7736–8802. PubMed PMC

Schaper F, Rose-John S. Interleukin-6: Biology, signaling and strategies of blockade. Cytokine Growth Factor Rev. 2015;26:475–87. PubMed

Liu Z, Zhao Y, Fang J, Cui R, Xiao Y, Xu Q. SHP2 negatively regulates HLA-ABC and PD-L1 expression via STAT1 phosphorylation in prostate cancer cells. Oncotarget. 2017;8:53518–30. PubMed PMC

Chen H, Zhou L, Wu X, Li R, Wen J, Sha J, Wen X. The PI3K/AKT pathway in the pathogenesis of prostate cancer. Front Biosci - Landmark. 2016;21:1084–91. PubMed

Sheng X, Bin LW, Wang DL, Chen KH, Cao JJ, Luo Z, He J, Li MC, Liu WJ, Yu C. YAP is closely correlated with castration-resistant prostate cancer, and downregulation of YAP reduces proliferation and induces apoptosis of PC-3 cells. Mol Med Rep. 2015;12:4867–76. PubMed PMC

Jamaspishvili T, Berman DM, Ross AE, Scher HI, De Marzo AM, Squire JA. Lotan TL (2018) Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol. 2018;15(4):222–34. PubMed PMC

Choudhury AD. PTEN-PI3K pathway alterations in advanced prostate cancer and clinical implications. Prostate. 2022;82(Suppl 1):S60–72. PubMed

Chen Z, Trotman LC, Shaffer D, et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 2005;436:725–30. PubMed PMC

Parisotto M, Grelet E, El Bizri R, Metzger D. Senescence controls prostatic neoplasia driven by Pten loss. Mol Cell Oncol. 2019;6:1511205. PubMed PMC

Young ARJ, Narita M. SASP reflects senescence. EMBO Rep. 2009;10:228–30. PubMed PMC

Huang W, Hickson LTJ, Eirin A, Kirkland JL, Lerman LO. Cellular senescence: the good, the bad and the unknown. Nat Rev Nephrol. 2022;18:611–27. PubMed PMC

Stultz J, Fong L. How to turn up the heat on the cold immune microenvironment of metastatic prostate cancer. Prostate Cancer Prostatic Dis. 2021;24:697–717. PubMed PMC

Suzuki A, Yamaguchi MT, Ohteki T, et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity. 2001;14:523–34. PubMed

Wu X, Wu J, Huang J, Powell WC, Zhang JF, Matusik RJ, Sangiorgi FO, Maxson RE, Sucov HM, Roy-Burman P. Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation. Mech Dev. 2001;101:61–9. PubMed

Limberger T, Schlederer M, Trachtová K, et al. KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis. Mol Cancer. 2022;21:1–19. PubMed PMC

Birbach A, Eisenbarth D, Kozakowski N, Ladenhauf E, Schmidt-Supprian M, Schmid JA. Persistent inflammation leads to proliferative neoplasia and loss of smooth muscle cells in a prostate tumor model. Neoplasia. 2011;13:692–703. PubMed PMC

Redmer T, Raigel M, Sternberg C, et al. JUN mediates the senescence associated secretory phenotype and immune cell recruitment to prevent prostate cancer progression. Mol Cancer. 2024;23:114. PubMed PMC

Schmidt U, Weigert M, Broaddus C, Myers G (2018) Cell Detection with Star-Convex Polygons. In: Frangi A., Schnabel J., Davatzikos C., Alberola-López C., Fichtinger G. (eds) Medical Image Computing and Computer Assisted Intervention – MICCAI 2018. Lecture Notes in Computer Science, vol 11071. Springer, Cham. p. 265–273. https://link.springer.com/chapter/10.1007/978-3-030-00934-2_30. DOI

Ding Z, Wu CJ, Chu GC, et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature. 2011;470:269–76. PubMed PMC

Drost J, Karthaus WR, Gao D, Driehuis E, Sawyers CL, Chen Y, Clevers H. Organoid culture systems for prostate epithelial and cancer tissue. Nat Protoc. 2016;11:347–58. PubMed PMC

Abeshouse A, Ahn J, Akbani R, et al. The Molecular Taxonomy of Primary Prostate Cancer. Cell. 2015;163:1011–25. PubMed PMC

Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:1. PubMed PMC

Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4. PubMed PMC

CRAN - Package survminer. https://cran.r-project.org/web/packages/survminer/index.html. Accessed 9 Feb 2023.

Yoshihara K, Shahmoradgoli M, Martínez E, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612. PubMed PMC

Stuhlmann-Laeisz C, Lang S, Chalaris A, et al. Forced dimerization of gp130 leads to constitutive STAT3 activation, cytokine-independent growth, and blockade of differentiation of embryonic stem cells. Mol Biol Cell. 2006;17:2986–95. PubMed PMC

Wang S, Gao J, Lei Q, et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell. 2003;4(3):209–21. PubMed

Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50. PubMed PMC

Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417. PubMed PMC

Swoboda A, Soukup R, Eckel O, et al. STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pathway. Oncogene. 2021;40:1091–105. PubMed PMC

Azare J, Leslie K, Al-Ahmadie H, Gerald W, Weinreb PH, Violette SM, Bromberg J. Constitutively activated Stat3 induces tumorigenesis and enhances cell motility of prostate epithelial cells through integrin beta 6. Mol Cell Biol. 2007;27:4444–53. PubMed PMC

Carpenter RL, Lo HW. STAT3 Target Genes Relevant to Human Cancers. Cancers (Basel). 2014;6:897–925. PubMed PMC

Darnell JE. Kerr lan M, Stark GR (1994) Jak-STAT Pathways and Transcriptional Activation in Response to IFNs and Other Extracellular Signaling Proteins. Science. 1979;264:1415–21. PubMed

Wen Z, Zhong Z, Darnell JE. Maximal Activation of Transcription by Statl and Stat3 Requires Both Tyrosine and Serine Phosphorylation. Cell. 1995;82:241–50. PubMed

Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6:1–6. PubMed PMC

Aguirre-Gamboa R, Gomez-Rueda H, Martínez-Ledesma E, Martínez-Torteya A, Chacolla-Huaringa R, Rodriguez-Barrientos A, Tamez-Peña JG, Treviño V. SurvExpress: an online biomarker validation tool and database for cancer gene expression data using survival analysis. PLoS ONE. 2013;8: e74250. PubMed PMC

Taylor BS, Schultz N, Hieronymus H, et al. Integrative Genomic Profiling of Human Prostate Cancer. Cancer Cell. 2010;18:11–22. PubMed PMC

Gulzar ZG, Mckenney JK, Brooks JD. Increased expression of NuSAP in recurrent prostate cancer is mediated by E2F1. Oncogene. 2013;32:70–7. PubMed PMC

Tan MH, Li J, Xu HE, Melcher K, Yong EL. Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol Sin. 2015;36:3–23. 10.1038/aps.2014.18. https://www.nature.com/articles/aps201418#citeas. PubMed PMC

Oberhuber M, Pecoraro M, Rusz M, et al (2020) STAT3-dependent analysis reveals PDK4 as independent predictor of recurrence in prostate cancer. Mol Syst Biol. 10.15252/MSB.20199247 PubMed PMC

Wiebringhaus R, Pecoraro M, Neubauer HA, et al. Proteomic analysis identifies ndufs1 and atp5o as novel markers for survival outcome in prostate cancer. Cancers (Basel). 2021;13:6036. PubMed PMC

Kiuchi N, Nakajima K, Ichiba M, Fukada T, Narimatsu M, Mizuno K, Hibi M, Hirano T. STAT3 Is Required for the gp130-mediated Full Activation of the c-myc Gene. J Exp Med. 1999;189:63–73. PubMed PMC

Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15(4):234–48. PubMed PMC

Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12:31–46. PubMed

Alimonti A, Nardella C, Chen Z, et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J Clin Invest. 2010;120:681–93. PubMed PMC

Bischof O, Kirsh O, Pearson M, Itahana K, Pelicci PG, Dejean A. Deconstructing PML-induced premature senescence. EMBO J. 2002;21:3358–69. PubMed PMC

Guccini I, Revandkar A, D’Ambrosio M, et al. Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis. Cancer Cell. 2021;39:68–82.e9. PubMed

Ouelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell. 1995;83:993–1000. PubMed

Reiser J, Banerjee A. Effector, Memory, and Dysfunctional CD8(+) T Cell Fates in the Antitumor Immune Response. J Immunol Res. 2016. 10.1155/2016/8941260. PubMed PMC

Jorgovanovic D, Song M, Wang L, Zhang Y. Roles of IFN-γ in tumor progression and regression: a review. Biomark Res. 2020;8:49. 10.1186/s40364-020-00228-x. PubMed PMC

Farhood B, Najafi M, Mortezaee K. CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review. J Cell Physiol. 2019;234:8509–21. PubMed

Sun W, Shi H, Yuan Z, Xia L, Xiang X, Quan X, Shi W, Jiang L. Prognostic Value of Genes and Immune Infiltration in Prostate Tumor Microenvironment. Front Oncol. 2020. 10.3389/FONC.2020.584055/FULL. PubMed PMC

Tošić I, Frank DA. STAT3 as a mediator of oncogenic cellular metabolism: Pathogenic and therapeutic implications. Neoplasia. 2021;23:1167–78. PubMed PMC

Zhang HF, Lai R. STAT3 in cancer-friend or foe? Cancers (Basel). 2014;6:1408–40. PubMed PMC

Tolomeo M, Cascio A. The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy. Int J Mol Sci. 2021;22:603. PubMed PMC

De La Iglesia N, Konopka G, Puram SV, Chan JA, Bachoo RM, You MJ, Levy DE, DePinho RA, Bonni A. Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Genes Dev. 2008;22:449–62. PubMed PMC

Musteanu M, Blaas L, Mair M, et al. Stat3 is a negative regulator of intestinal tumor progression in Apc(Min) mice. Gastroenterology. 2010. 10.1053/J.GASTRO.2009.11.049. PubMed

Wang H, Lafdil F, Wang L, Park O, Yin S, Niu J, Miller AM, Sun Z, Gao B. Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis. Am J Pathol. 2011;179:714–24. PubMed PMC

Schmitt CA, Wang B, Demaria M. Senescence and cancer — role and therapeutic opportunities. Nat Rev Clin Oncol. 2022;19:619–36. PubMed PMC

Rufini A, Tucci P, Celardo I, Melino G. Senescence and aging: the critical roles of p53. Oncogene. 2013;32:5129–43. 10.1038/onc.2012.640. PubMed

Bousset L, Gil J. Targeting senescence as an anticancer therapy. Mol Oncol. 2022;16:3855–80. PubMed PMC

Toso A, Revandkar A, DiMitri D, et al. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 2014;9:75–89. PubMed

Takeda K, Kaisho T, Yoshida N, Takeda J, Kishimoto T, Akira S. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J Immunol. 1998;161(9):4652–60. Erratum in: J Immunol. 2015;194(7):3526. 10.4049/jimmunol.1500168. https://pubmed.ncbi.nlm.nih.gov/9794394/. PubMed

Minegishi Y, Saito M, Tsuchiya S, et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007;448:1058–62. PubMed

Alonzi T, Maritano D, Gorgoni B, Rizzuto G, Libert C, Poli V. Essential Role of STAT3 in the Control of the Acute-Phase Response as Revealed by Inducible Gene Activation in the Liver. Mol Cell Biol. 2001;21:1621–32. PubMed PMC

Kremer A, Kremer T, Kristiansen G, Tolkach Y. Where is the limit of prostate cancer biomarker research? Systematic investigation of potential prognostic and diagnostic biomarkers. BMC Urol. 2019;19:46. PubMed PMC

Loeb S, Bjurlin MA, Nicholson J, Tammela TL, Penson DF, Carter HB, Carroll P, Etzioni R. Overdiagnosis and overtreatment of prostate cancer. Eur Urol. 2014;65:1046–55. PubMed PMC

Russo M, Nastasi C. Targeting the Tumor Microenvironment: A Close Up of Tumor-Associated Macrophages and Neutrophils. Front Oncol. 2022. 10.3389/fonc.2022.871513. PubMed PMC

Strasner A, Karin M. Immune infiltration and prostate cancer. Front Oncol. 2015;5:128. PubMed PMC

Wang L, Pan S, Zhu B, Yu Z, Wang W. Comprehensive analysis of tumour mutational burden and its clinical significance in prostate cancer. BMC Urol. 2021;21:1–10. PubMed PMC

Maleki Vareki S. High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J Immunother Cancer. 2018;6:157. PubMed PMC

Reimann M, Schrezenmeier J, Richter-Pechanska P, et al. Adaptive T-cell immunity controls senescence-prone MyD88- or CARD11-mutant B-cell lymphomas. Blood. 2021;137:2785–99. PubMed

Miyake M, Hori S, Owari T, Oda Y, Tatsumi Y, Nakai Y, Fujii T, Fujimoto K. Clinical Impact of Tumor-Infiltrating Lymphocytes and PD-L1-Positive Cells as Prognostic and Predictive Biomarkers in Urological Malignancies and Retroperitoneal Sarcoma. Cancers (Basel). 2020;12:1–28. PubMed PMC

Allen GM, Frankel NW, Reddy NR, Bhargava HK, Yoshida MA, Stark SR, Purl M, Lee J, Yee JL, Yu W, Li AW, Garcia KC, El-Samad H, Roybal KT, Spitzer MH, Lim WA. Synthetic cytokine circuits that drive T cells into immune-excluded tumors. Science. 2022;378(6625):eaba1624. 10.1126/science.aba1624. PubMed PMC