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The combination therapy of Everolimus and anti-PD-1 improves the antitumor effect by regulating CD8+ T cells in bladder cancer

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Abstract

This study aimed to investigate the efficacy of Everolimus (EVE) in combination with immune checkpoint inhibitors (ICIs) in bladder cancer treatment and the underlying mechanisms. In vitro, MB49 cells were exposed to gradient concentrations (0 nM–100 nM) of EVE for 48 h, to investigate the cell viability and cell proliferative potential. In vivo, we applied a subcutaneous tumor mouse model of bladder cancer and the mice were treated with EVE monotherapy (different doses) or in combination with anti-programmed cell death protein 1 (PD-1) agents to study the impacts on tumor growth and explore the immune mechanism. The influences of treatments on peripheral immune profiles and tumor immune microenvironment were also discussed. EVE could inhibit the growth of MB49 cells in vitro. Though high-dose EVE monotherapy could induce tumor regression in vivo, it also contributed to immunosuppression. High-dose EVE inhibited the expression of PD-L1 by inhibiting Th1 cytokine secretion, while combined therapy with PD-1 inhibitors showed no extra profit. Low-dose EVE in combination with PD-1 inhibitors could effectively suppress tumor growth by increasing periphery CD8+ T cell frequency and GZMB+ CD8+ T cell frequency in the tumor microenvironment. High-dose EVE monotherapy induced tumor regression, but with immunosuppression to some content. Combination therapy with low-dose EVE and PD-1 inhibitor could effectively inhibit the growth of bladder tumors by enhancing the antitumor immunity of CD8+ T cells in both periphery and tumor microenvironment.

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Data availability

The datasets used in this study are available from the corresponding author upon reasonable request.

Code availability

Not appliable.

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Acknowledgements

We thank Dr. Longcheng Li for sharing the murine tumor cell line MB49.

Funding

This work was supported by the Science and Technology Commission of Shanghai Municipality (No. 21511902300).

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Author notes

  1. Weimin Xia and Shun Zhang have contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Yangpu, 200092, Shanghai, China

    Weimin Xia, Shun Zhang, Huangqi Duan, Chen Wang, Subo Qian & Haibo Shen

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  1. Weimin Xia
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  2. Shun Zhang
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  3. Huangqi Duan
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  4. Chen Wang
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Contributions

Weimin Xia: study design, animal experinment, data analysis, and manuscript writing. Shun Zhang: study design, animal experinment, and manuscript writing. Huangqi Duan: animal experinment and data analysis. Chen Wang: animal experinment and data analysis. Subo Qian: data analysis, manuscript writing and editing, and revision study design. Haibo Shen: study design, data analysis, manuscript editing, and supervision.

Corresponding author

Correspondence to Haibo Shen.

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The authors declare that they have no conflict of interest.

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All procedures performed in this study were in accordance with the ethical standards of the Ethics Committee of Xinhua Hospital and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Xia, W., Zhang, S., Duan, H. et al. The combination therapy of Everolimus and anti-PD-1 improves the antitumor effect by regulating CD8+ T cells in bladder cancer. Med Oncol 39, 37 (2022). https://doi.org/10.1007/s12032-021-01624-5

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  • DOI: https://doi.org/10.1007/s12032-021-01624-5

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