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Feedback loop between fatty acid transport protein 2 and receptor interacting protein 3 pathways promotes polymorphonuclear neutrophil myeloid-derived suppressor cells-potentiated suppressive immunity in bladder cancer

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Abstract

Background

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) promote tumor immune tolerance and cause tumor immunotherapy failure. In this study, we found that high PMN-MDSCs infiltration, overexpressed fatty acid transporter protein 2 (FATP2) and underexpressed receptor-interacting protein kinase 3 (RIPK3) existed in the mouse and human bladder cancer tissues. However, the related mechanisms remain largely unknown.

Methods and results

Both FATP2 and RIPK3 expressions were associated with clinical stage. FATP2 knockout or up-regulating RIPK3 reduced the synthesis of prostaglandin E2 (PGE2) in PMN-MDSCs, attenuated the suppressive activity of PMN-MDSCs on CD8+ T cells functions and inhibited the tumor growth. There was a PGE2-mediated feedback loop between FATP2 and RIPK3 pathways, which markedly promoted the immunosuppressive activity of PMN-MDSCs. Combination therapy with inhibition of FATP2 and activation of RIPK3 can effectively inhibit tumor growth.

Conclusions

This study demonstrated that a feedback loop between FATP2 and RIPK3 pathways in PMN-MDSCs significantly promoted the synthesis of PGE2, which severely impaired the CD8+ T cell functions. This study may provide new ideas for immunotherapy of human bladder cancer.

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Funding

This study was supported by National Natural Science Foundation of China (No.81902595) and Science and Technology Program of Guangzhou (No.202002030482).

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Authors and Affiliations

  1. Department of Urology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China

    Xiaojun Shi, Shiyu Pang, Jiawei Zhou, Guang Yan & Wanlong Tan

  2. Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Jie Sun

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  1. Xiaojun Shi
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  2. Shiyu Pang
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  4. Guang Yan
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Contributions

Xiaojun Shi and Wanlong Tan conceived of this study, collected data, and prepared the manuscript. Jie Sun, Shiyu Pang and Jiawei Zhou collected data, performed data analysis, and prepared the manuscript. Guang Yan and Wanlong Tan collected data and revised the manuscript.

Corresponding author

Correspondence to Xiaojun Shi.

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Conflict of interest

The authors declare that have no conflict of interest.

Ethical approval

The study was approved by the Ethics Committee of Nanfang hospital. All patients signed the approved consent forms. All experimental procedures were performed in accordance with the relevant laws and institutional guidelines of Southern Medical University.

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Supplementary Fig. 1 Expressions of LOX-1, FATP2 and RIPK3 in human bladder tumor tissues.

Immunohistochemistry assays were performed to detect the expressions of LOX-1, FATP2 and RIPK3 in human tumor tissues with adjacent tissues as control (n = 18) (A: LOX-1; B: FATP2; C: RIPK3). (*P < 0.05)

Supplementary Fig. 2 The gating strategy used in Figs. 3, 4 and 5.

PMN-MDSCs were cocultured with CD8+ T cells, and flow cytometry was performed to detect the IFN-γ+CD8+ T cells.

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Shi, X., Pang, S., Zhou, J. et al. Feedback loop between fatty acid transport protein 2 and receptor interacting protein 3 pathways promotes polymorphonuclear neutrophil myeloid-derived suppressor cells-potentiated suppressive immunity in bladder cancer. Mol Biol Rep 49, 11643–11652 (2022). https://doi.org/10.1007/s11033-022-07924-x

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  • DOI: https://doi.org/10.1007/s11033-022-07924-x

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