Skip to main content

Advertisement

SpringerLink
Log in

OncoTherad® is an immunomodulator of biological response that downregulate RANK/RANKL signaling pathway and PD-1/PD-L1 immune checkpoint in non-muscle invasive bladder cancer

  • Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Intoduction

Bladder cancer is the second most common urinary tract cancer. Above 70% of the occurrence of bladder cancer is superficial (pTis, pTa, and pT1), non-muscle invasive tumor (NMIBC), and the incidence of invasive disease is occasional. Treatments for NMIBC consist of transurethral resection (TUR) and subsequently intravesical immunotherapy with Bacillus Calmette-Guérin (BCG), intending to prevent tumor progression and decrease recurrence. However, 20–30% of these tumors have progression, and 70% have a recurrence after exclusive TUR treatment. The immunomodulator of biological response, OncoTherad®, is an attractive potential to revolutionize cancer therapy. In our previous studies with mice, the results showed that treatment with OncoTherad® reduced 100% of tumor progression in NMIBC through the activation of Toll-Like Receptors’ non-canonical pathway.

Materials and Methods

 In the present study, 36 female C57Bl/6J mice were divided into 6 groups (n = 6/group): Control, Cancer, Cancer + BCG, Cancer + OncoTherad® (MRB-CFI-1), Cancer + P14-16 and Cancer + CFI-1. NMIBC was chemically induced and the treatments were followed for 6 weeks. A week after the last dose of treatment, animals were euthanized, the bladder was collected and routinely processed for immunohistochemical analyses of RANK, RANKL, FOXP3, and PD-1/PD-L1, such as PD-1/PD-L1 western blotting.

Conclusion

The immunohistochemical results showed that OncoTherad® reduced RANK and RANKL immunoreactivities compared to the cancer group, which indicates a good prognosis. Immunohistochemical and western blotting analyses confirmed that OncoTherad® modulated PD-1/PD-L1 immune checkpoint.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of data and materials

The authors confirm that the data supporting the findings of this study are available within the article.

References

  • Aerts J, Lievense L, Hoogsteden H, Hegmans J (2013) Immunotherapy prospects in the treatment of lung cancer and mesothelioma. Transl Lung Cancer Res 3:34–45

    Google Scholar 

  • Ahern E, Smyth MJ, Dougall WC, Teng MWL (2018) Roles of the RANKL–RANK axis in antitumour immunity—implications for therapy. Nature Rev Clin Oncol 15:676–693

    Google Scholar 

  • Akiyama T, Shimo Y, Yanai H, Qin J, Ohshima D, Maruyama Y et al (2008) The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29:423–437

    CAS  PubMed  Google Scholar 

  • Akiyama T, Shinzawa M, Qin J, Akiyama N (2013) Regulations of gene expression in medullary thymic epithelial cells required for preventing the onset of autoimmune diseases. Front Immunol 4:249

    CAS  PubMed  PubMed Central  Google Scholar 

  • American Cancer Society (2021) Overview: bladder cancer. In: What are the key statistics about bladder cancer? American Cancer Society, Atlanta. http://www.cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-key-statistics. Accessed 2 May 2021

  • Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F (2017) Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol 71:96–108

    PubMed  Google Scholar 

  • Askeland EJ, Newton MR, O’Donnell MA, Luo Y (2012) Bladder cancer immunotherapy: BCG and beyond. Adv Urol 2012:181987. https://doi.org/10.1155/2012/181987

    Article  PubMed  PubMed Central  Google Scholar 

  • Berry DL, Blumenstein BA, Magyary DL, Lamm DL, Crawford ED (1996) Local toxicity patterns associated with intravesical bacillus Calmette-Guerin: a Southwest Oncology Group study. Int J Urol 3:98–100

    CAS  PubMed  Google Scholar 

  • Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Eng J Med 366:2455–2465

    CAS  Google Scholar 

  • Campbell DJ, Ziegler SF (2007) FOXP3 modifies the phenotypic and functional properties of regulatory T cells. Nature Rev Immunol 7:305–310

    CAS  Google Scholar 

  • Chawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S et al (2013) Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol 14:901–908

    CAS  PubMed  Google Scholar 

  • Chen G, Sircar K, Aprikian A, Potti A, Goltzman D, Rabbani SA (2006) Expression of RANK/RANKL/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation. Cancer 107:289–298

    CAS  PubMed  Google Scholar 

  • Chen YB, Mu CY, Huang JA (2012) Clinical significance of programmed death-1 ligand-1 expression in patients with non-small cell lung cancer: a 5-year-follow-up study. Tumori 98:751–755

    PubMed  Google Scholar 

  • Cheng ML, Fong L (2014) Effects of RANKL-targeted therapy in immunity and cancer. Front Oncol 3:329

    PubMed  PubMed Central  Google Scholar 

  • Chuang FH, Hsue SS, Wu CW, Chen YK (2009) Immunohistochemical expression of RANKL, RANK, and OPG in human oral squamous cell carcinoma. J Oral Pathol Med 38:753–758

    CAS  PubMed  Google Scholar 

  • Cree IA, Booton R, Cane P, Gosney J, Ibrahim M, Kerr K et al (2016) PD-L1 testing for lung cancer in the UK: recognizing the challenges for implementation. Histopathology 69:177–186 (Erratum in: Histopathology (2017). 70:318)

    PubMed  Google Scholar 

  • Chae YK, Pan A, Davis AA, Raparia K, Mohindra NA, Matsangou M, Giles FJ (2016) Biomarkers for PD-1/PD-L1 Blockade Therapy in Non–Small-cell Lung Cancer: Is PD-L1 Expression a Good Marker for Patient Selection?. Clinical Lung Cancer 17(5): 350–361. https://doi.org/10.1016/j.cllc.2016.03.011

    Article  CAS  Google Scholar 

  • David E, Blanchard F, Heymann MF, De Pinieux G, Gouin F, Rédini F et al (2011) The bone niche of chondrosarcoma: a sanctuary for drug resistance, tumour growth and also a source of new therapeutic targets sarcoma. Sarcoma 2011:932451. https://doi.org/10.1155/2011/932451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diggs LP, Hsueh EC (2017) Utility of PD-L1 immunohistochemistry assays for predicting PD-1/PD-L1 inhibitor response. Biomark Res 5:12

    PubMed  PubMed Central  Google Scholar 

  • Droeser RA, Hirt C, Viehl CT, Frey DM, Nebiker C, Huber X et al (2013) Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer 49:2233–2242

    CAS  PubMed  Google Scholar 

  • Durán N, Dias QC, Fávaro WJ (2019) OncoTherad: A new nanobiological response modifier, its toxicological and anticancer activities. J Phys Conf Ser 1323:012018

    Google Scholar 

  • Emens LA, Braiteh FS, Cassier P, Delord J-P, Eder JP, Fasso M et al (2015) Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer. Ann Meet Amer Ass Cancer Res 75(15 Suppl): 2859.

    Google Scholar 

  • Fávaro WJ, Iantas SR, Gonçalves JM, Dias QC, Reis IB, Billis A, Durán N, Alonso JC (2019) Role of OncoTherad immunotherapy in the regulation of toll-like receptors-mediated immune system and RANK/RANKL signaling: New therapeutic perspective for non-muscle invasive bladder cancer. J Clin Oncol 37:15

    Google Scholar 

  • Fávaro WJ, Durán N (2020) A method for producing a nanostructured complex (cfi-1), a protein associated nanostructured complex (mrb-cfi-1) and use. US Patent App 16/617,493

  • Fiumara P, Snell V, Li Y, Mukhopadhyay A, Younes M, Gillenwater AM, Cabanillas F et al (2001) Functional expression of receptor activator of nuclear factor kappaB in Hodgkin disease cell lines. Blood 98:2784–2790

    CAS  PubMed  Google Scholar 

  • Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol 4:330–336

    CAS  Google Scholar 

  • Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK et al (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206:3015–3029

    CAS  PubMed  PubMed Central  Google Scholar 

  • Frega S, Maso AD, Ferro A, Bonanno L, Conte DF, Passelo G (2019) Heterogeneous tumor features and treatment outcome between males and females with lung cancer (LC): do gender and sex matter? Crit Rev Oncol/hematol 138:87–103

    PubMed  Google Scholar 

  • Gandini S, Massi D, Mandalà M (2016) PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: a systematic review and meta-analysis. Crit Rev Oncol Hematol 100:88–98

    PubMed  Google Scholar 

  • Garcia PV, Apolinário LM, Böckelmann PK, Nunes IS, Durán N, Fávaro WJ (2015) Alterations in ubiquitin ligase Siah-2 and its corepressor N-CoR after P-MAPA immunotherapy and anti-androgen therapy: new therapeutic opportunities for non-muscle invasive bladder cancer. Int J Clin Exp Pathol 8:4427–4443

    PubMed  PubMed Central  Google Scholar 

  • Groot AF, Appelman-Dijkstra NM, Van der Burg SH, Kroep JR (2018) The anti-tumor effect of RANKL inhibition in malignant solid tumors–a systematic review. Cancer Treat Rev 62:18–28

    PubMed  Google Scholar 

  • Hall MC, Chang SS, Dalbagni G, Prudrakethi RS, Seigne JD, Skinner EC et al (2007) Guideline for the management of nonmuscle invasive bladder câncer (stages Ta, T1, and Tis): 2007 update. J Urol 178:2314–2330

    PubMed  Google Scholar 

  • Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K et al (2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 104:3360–3365

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hamanishi J, Murakami R, Baba T, Yamaguchi K, Abiko K, Mandai M (2019) Passenger fusion genes are correlated to antitumor effect of anti-PD-1 antibody nivolumab for ovarian cancer. Gynecol Oncol 154:86

    Google Scholar 

  • Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS et al (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563–567

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heymann MF, Riet A, Le Goff B, Battaglia S, Paineau J, Heymann D (2008) OPG, RANK and RANK ligand expression in thyroid lesions. Regul Pept 148:46–53

    CAS  PubMed  Google Scholar 

  • Hodi FS, O’Day SJ, Weber MDF, RW, Sosman JA, Haanen JB, et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061

    CAS  PubMed  Google Scholar 

  • Hu H, Wang J, Gupta A, Shidfar A, Branstetter D, Lee O et al (2014) RANKL expression in normal and malignant breast tissue responds to progesterone and is up-regulated during the luteal phase. Breast Cancer Res Treat 146:515–523

    CAS  PubMed  Google Scholar 

  • Iria M (2021) RANK signaling in the differentiation and regeneration of thymic epithelial cells. Front Immunol 11:623265

    Google Scholar 

  • Jahrreiss V, Pradere B, Laukhtina E, Mori K, Shariat SF (2020) Catalog of exogenous risk factors for bladder carcinogenesis. Curr Opin Urol 30:449–456

    PubMed  Google Scholar 

  • Jones VS, Huang RY, Chen LP, Chen ZS, Fu L, Huang RP (2016) Cytokines in cancer drug resistance: cues to new therapeutic strategies. Biochim Biophys Acta 1865:255–265

    CAS  PubMed  Google Scholar 

  • Kamat AM, Colombel M, Sundi D, Lamm D, Boehle A, Brausi M et al (2017) BCG-unresponsive non-muscle-invasive bladder cancer: recommendations from the IBCG. Nat Rev Urol 14:244–255

    PubMed  Google Scholar 

  • Kerr KM, Nicolson MC (2016) Non-small cell lung cancer, PD-L1, and the pathologist. Arch Pathol Lab Med 140:249–254

    PubMed  Google Scholar 

  • Kemp TJ, Ludwig AT, Earel JK, JiM Moore, VanOosten RL, Moses B, Kevin L, Nauseef WM, Griffith TS (2005) Neutrophil stimulation with Mycobacterium bovis bacillus Calmette-Guérin (BCG) results in the release of functional soluble TRAIL/Apo-2L. Blood 106(10):3474–3482. https://doi.org/10.1182/blood-2005-03-1327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khattri R, Cox T, Yasayko SA, Ramsdell F (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nature Immunol 4:337–342

    CAS  Google Scholar 

  • Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C et al (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–323

    CAS  PubMed  Google Scholar 

  • Kulkarni GS (2020) Nadofaragene firadenovec: a new gold standard for BCG-unresponsive bladder cancer? Lancet Oncol. https://doi.org/10.1016/s1470-2045(20)30586-6

    Article  PubMed  Google Scholar 

  • Lee JA, Jung JS, Kim DH, Lim JS, Kim MS, Kong CB et al (2011) RANKL expression is related to treatment outcome of patients with localized, high-grade osteosarcoma. Pediatr Blood Cancer 56:738–743

    PubMed  Google Scholar 

  • Li X, Liu Y, Wu B, Dong Z, Wang Y, Lu J et al (2014) Potential role of the OPG/RANK/RANKL axis in prostate cancer invasion and bone metastasis. Oncol Rep 32:2605–2611

    CAS  PubMed  Google Scholar 

  • Li Z, Dong P, Ren M, Song Y, Qiang X, Yang Y et al (2016) PD-L1 expression is associated with tumor FOXP3+ regulatory T-cell infiltration of breast cancer and poor prognosis of patient. J Cancer 7:784–793

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li C, Jiang P, Wei S, Xu X, Wang J (2020) Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects. Mol Cancer 19:116

    PubMed  PubMed Central  Google Scholar 

  • Ming J, Cronin SJF, Penninger JM (2020) Targeting the RANKL/RANK/OPG axis for cancer therapy. Front Oncol 10:1283

    PubMed  PubMed Central  Google Scholar 

  • Mori K, Le Goff B, Charrier C, Battaglia S, Heymann D, Rédini F (2006) DU145 human prostate cancer cells express functional receptor activator of NFkappa B: new insights in the prostate cancer bone metastasis process. Bone 40:981–890

    PubMed  Google Scholar 

  • Mori K, Le Goff B, Berreur M, Riet A, Moreau A, Blanchard F et al (2007) Human osteosarcoma cells express functional receptor activator of nuclear factor-kappa B. J Pathol 11:555–562

    Google Scholar 

  • Mueller CG, Hess E (2012) Emerging functions of RANKL in lymphoid tissues. Front Immunol 3:261

    PubMed  PubMed Central  Google Scholar 

  • Muenst S, Schaerli AR, Gao F, Däster S, Trella E, Droeser RA, Muraro MG, Zajac P, Zanetti R, Gillanders WE, Weber WP, Soysal SD (2014) Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Research and Treatment 146(1):15–24. https://doi.org/10.1007/s10549-014-2988-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ni XY, Sui HX, Liu Y, Ke SZ, Wang YN, Gao FG (2012) TGF-beta of lung cancer microenvironment upregulates B7H1 and GITRL expression in dendritic cells and is associated with regulatory T cell generation. Oncol Rep 28:615–621

    CAS  PubMed  Google Scholar 

  • Park HS, Lee A, Chae BJ, Bae JS, Song BJ, Jung SS (2014) Expression of receptor activator of nuclear factor kappa-B as a poor prognostic marker in breast cancer. J Surg Oncol 110:807–812

    CAS  PubMed  Google Scholar 

  • Perabo FG, Willert PL, Wirger A, Schmidt DH, Von Ruecker A, Mueller SC (2005) Superantigen-activated mononuclear cells induce apoptosis in transitional cell carcinoma. Anticancer Res 25:3565–3573

    CAS  PubMed  Google Scholar 

  • Pfitzner BM, Branstetter D, Loibl S, Denkert C, Lederer B, Schmitt WD et al (2014) RANK expression as a prognostic and predictive marker in breast cancer. Breast Cancer Res Treat 145:307–315

    CAS  PubMed  Google Scholar 

  • Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C et al (2014) MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515:558–562

    CAS  PubMed  Google Scholar 

  • Quiao H, Cui Z, Yang S, Ju D, Wang Y, Yang Y, Han X, Fan Q, Qin A, Wang T, He XP, Bu W, Tang T (2017) Targeting osteocytes to attenuate early breast cancer bone metastasis by theranostic upconversion nanoparticles with responsive plumbagin release. ACS Nano 7:7259–7273

    Google Scholar 

  • Rebelatto MC, Midha A, Mistry A, Sabalos C, Schechter N, Li X et al (2016) Development of a programmed cell death ligand-1 immunohistochemical assay validated for analysis of non-small cell lung cancer and head and neck squamous cell carcinoma. Diagn Pathol 11:95

    PubMed  PubMed Central  Google Scholar 

  • Reis IB, Tibo LHS, Socca EAR, Souza BR, Durán N, Fávaro WJ (2022a) OncoTherad® (MRB-CFI-1) nano-immunotherapy reduced tumoral progression in non-muscle invasive bladder cancer through activation of Toll-like signaling pathway. Tissue Cell 76:71762

    Google Scholar 

  • Reis SK, Socca EAR, de Souza BR, Genaro SC, Durán N, Fávaro WJ (2022b) Effects of combined OncoTherad immunotherapy and probiotic supplementation on modulating the chronic inflammatory process in colorectal carcinogenesis. Tissue Cell 75:01747

    Google Scholar 

  • Renema N, Navet B, Heymann MF, Lezot F, Heymann D (2016) RANK-RANKL signalling in cancer. Biosci Rep 36:1–18

    Google Scholar 

  • Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D et al (2015) Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372:30–39

    PubMed  Google Scholar 

  • Saleh R, Elkord E (2020) FoxP3þT regulatory cells in cancer: Prognostic biomarkers and therapeutic targets. Cancer Lett 490:174–185

    CAS  PubMed  Google Scholar 

  • Santini D, Perrone G, Roato I, Godio L, Pantano F, Grasso D et al (2011a) Expression pattern of receptor activator of NFkB (RANK) in a series of primary solid tumors and related metastases. J Cell Physiol 226:780–784

    CAS  PubMed  Google Scholar 

  • Santini D, Schiavon G, Vincenzi B, Gaeta L, Pantano F, Russo A et al (2011b) Receptor activator of NF-kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. PLoS One 6:19234

    Google Scholar 

  • Schreiber TH (2007) The use of FoxP3 as a biomarker and prognostic factor for malignant human tumors. Cancer Epidemiol Biomarkers Prev a Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol 16:1931–1934

    CAS  Google Scholar 

  • Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ (2007) The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nature Immunol 8:239–245

    CAS  Google Scholar 

  • Siegel R, Naishadham D, Jemal A (2012) Cancer statistics. CA. Cancer J Clin 62:10–29

    Google Scholar 

  • Simatou A, Sarantis P, Koustas E, Papavassiliou AG, Karamouzis MV (2020) The role of the RANKL/RANK axis in the prevention and treatment of breast cancer with immune checkpoint inhibitors and anti-RANKL. Int J Mol Sci 21:7570

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sisay M, Mengistu G, Edessa D (2017) The RANK/RANKL/OPG system in tumorigenesis and metastasis of cancer stem cell: potential targets for anticancer therapy. Onco Targets Ther 10:3801–3810

    PubMed  PubMed Central  Google Scholar 

  • Sobacchi C, Menale C, Villa A (2020) The RANKL-RANK axis: a bone to thymus round trip. Front Immunol 10:629–638

    Google Scholar 

  • Stopglia RM, Matheus WE, Garcia PV, Billis A, Castilho MA, Figueiredo de Jesus VH et al (2015) Molecular assessment of non-muscle invasive and muscle invasive bladder tumors: mapping of putative urothelial stem cells and toll-like receptors (TLR) signaling. J Cancer Ther 6:129–140

    Google Scholar 

  • Sun Y, Wang Y, Zhao J, Gua M, Giscombe R, Lefvert AK et al (2006) B7–H3 and B7–H4 expression in non-small-cell lung cancer. Lung Cancer 53:143–151

    PubMed  Google Scholar 

  • Swann JB, Smyth MJ (2007) Immune surveillance of tumors. J Clin Invest 117:1137–1146

    CAS  PubMed  PubMed Central  Google Scholar 

  • Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH et al (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20:5064–5074

    CAS  PubMed  PubMed Central  Google Scholar 

  • Taube JM, Galon J, Sholl LM, Rodig SJ, Cottrell TR, Giraldo NA et al (2018) Implications of the tumor immune microenvironment for staging and therapeutics. Mod Pathol 31:214–234

    CAS  PubMed  Google Scholar 

  • Theoleyre S, Wittrant Y, KwanTat S, Fortun Y, Redini F, Heymann D (2004) The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev 15:457–475

    CAS  PubMed  Google Scholar 

  • Trieb K, Windhager R (2015) Receptor activator of nuclear factor κB expression is a prognostic factor in human osteosarcoma. Oncol Lett 10:1813–1815

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wan L, Pantel K, Kang Y (2013) Tumor metastasis: moving new biological insights into the clinic. Nat Med 19:1450–1464

    CAS  PubMed  Google Scholar 

  • Wang X, Teng F, Kong L, Yu J (2016) PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther 9:5023–5039

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wittrant Y, Théoleyre S, Chipoy C, Padrines M, Blanchard F, Heymann D, Rédini F (2004) RANKL/RANK/OPG: new therapeutic targets in bone tumours and associated osteolysis. Biochim Biophys Acta 1704:49–57

    CAS  PubMed  Google Scholar 

  • Wu X, Li F, Dang L, Liang C, Lu A, Zhang G (2020) RANKL/RANK system-based mechanism for breast cancer bone metastasis and related therapeutic strategies. Front Cell Dev Biol 8:76

    PubMed  PubMed Central  Google Scholar 

  • Yagi H, Nomura T, Nakamura K, Yamazaki S, Kitawaki T, Hori S et al (2004) Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. Inter Immunol 16:1643–1656

    CAS  Google Scholar 

  • Yu H, Boyle TA, Zhou C, Rimm DL, Hirsch FR (2016) PD-L1 expression in lung cancer. J Thorac Oncol 11:964–975

    PubMed  PubMed Central  Google Scholar 

  • Zhao B, Chang L, Fu H, Sun G, Yang W (2018) The role of autoimmune regulator (AIRE) in peripheral tolerance. J Immunol Res 2018:1–6

    Google Scholar 

Download references

Acknowledgements

This work was supported by the São Paulo Research Council [FAPESP grant number: 2018/10052-1; 2020/03419-6], the Brazilian National Council for Scientific and Technological Development [CNPq grant number: 552120/2011-1] and the Coordinating Agency for Advanced Training of Graduate Personnel [CAPES—grant number: 001].

Funding

This work was supported by the São Paulo Research Council [FAPESP grant number: 2018/10052-1; 2020/03419-6], the Brazilian National Council for Scientific and Technological Development [CNPq grant number: 552120/2011-1] and the Coordinating Agency for Advanced Training of Graduate Personnel [CAPES—grant number: 001].

Author information

Authors and Affiliations

  1. Department of Diagnosis and Surgery, School of Dentistry at Araraquara, São Paulo State University (UNESP), Rua Humaitá, 1680–Centro, Araraquara, SP, CEP 14801-903, Brazil

    Ianny Brum Reis

  2. Institute of Biology, Universidade Estadual de Campinas/UNICAMP, Campinas, SP, Brazil

    Luiz Henrique Soares Tibo, Bianca Ribeiro de Souza, Nelson Durán & Wagner José Fávaro

  3. Nanomedicine Research Unit (Nanomed), Federal University of ABC (UFABC), Santo André, SP, Brazil

    Nelson Durán

Authors
  1. Ianny Brum Reis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luiz Henrique Soares Tibo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bianca Ribeiro de Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nelson Durán
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wagner José Fávaro
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All the persons who meet authorship criteria are listed as the authors, and all the authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript. Furthermore, each author certifies that this material or similar material has not been and will not be submitted to or published in any other publication before. Conceptualization: IBR and WJF. Methodology: IBR, LHST, and WJF. Validation: IBR and LHST. Formal analysis: IBR and BRdS. Investigation: IBR, LHST, and BRdS. Resources: IBR, ND, and WJF. Data curation: IBR, LHST, and BRdS. Writing—original draft: IBR. Writing—review and editing: IBR, LHST, BRdS, ND, and WJF. Visualization: IBR. Supervision: IBR and WJF. Project administration: IBR and WJF. Funding acquisition: ND and WJF.

Corresponding author

Correspondence to Ianny Brum Reis.

Ethics declarations

Conflict of interest

The authors report the non-existence of any kind of conflict of interests.

Ethical approval

It was added in the text.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reis, I.B., Tibo, L.H.S., de Souza, B.R. et al. OncoTherad® is an immunomodulator of biological response that downregulate RANK/RANKL signaling pathway and PD-1/PD-L1 immune checkpoint in non-muscle invasive bladder cancer. J Cancer Res Clin Oncol 149, 5025–5036 (2023). https://doi.org/10.1007/s00432-022-04449-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-022-04449-5

Keywords

Search

Navigation