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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

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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.

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Availability of data and materials

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

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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].

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  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

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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.

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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

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