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Translational Therapeutics

Tumor-associated neutrophils suppress CD8+ T cell immunity in urothelial bladder carcinoma through the COX-2/PGE2/IDO1 Axis

British Journal of Cancer volume 130, pages 880–891 (2024)Cite this article

Subjects

Abstract

Background

Many urothelial bladder carcinoma (UBC) patients don’t respond to immune checkpoint blockade (ICB) therapy, possibly due to tumor-associated neutrophils (TANs) suppressing lymphocyte immune response.

Methods

We conducted a meta-analysis on the predictive value of neutrophil-lymphocyte ratio (NLR) in ICB response and investigated TANs’ role in UBC. We used RNA-sequencing, HALO spatial analysis, single-cell RNA-sequencing, and flow cytometry to study the impacts of TANs and prostaglandin E2 (PGE2) on IDO1 expression. Animal experiments evaluated celecoxib’s efficacy in targeting PGE2 synthesis.

Results

Our analysis showed that higher TAN infiltration predicted worse outcomes in UBC patients receiving ICB therapy. Our research revealed that TANs promote IDO1 expression in cancer cells, resulting in immunosuppression. We also found that PGE2 synthesized by COX-2 in neutrophils played a key role in upregulating IDO1 in cancer cells. Animal experiments showed that targeting PGE2 synthesis in neutrophils with celecoxib enhanced the efficacy of ICB treatment.

Conclusions

TAN-secreted PGE2 upregulates IDO1, dampening T cell function in UBC. Celecoxib targeting of PGE2 synthesis represents a promising approach to enhance ICB efficacy in UBC.

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Fig. 1: Meta-analysis of the association between NLR and prognosis in UBC patients receiving immune checkpoint blockade therapies.
Fig. 2: Neutrophil and CD8+ T cell infiltration predicts the response to immunotherapy in UBCs.
Fig. 3: IDO1 mediates the immunosuppressive effects of the interaction between TANs and cancer cells.
Fig. 4: Combination treatment of IDO1 inhibition and anti-PD1 delays tumor growth.
Fig. 5: PGE2 secreted by neutrophils upregulated IDO1 via the PKC-GSK pathway.
Fig. 6: Celecoxib enhances the therapeutic activity of PD-1 blockade in combination therapy.

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Data availability

The data from the IMvigor210 cohort are freely available under the Creative Commons 3.0 license and can be downloaded from http://research-pub.gene.com/IMvigor210CoreBiologies. The schematic and graphic illustration figure was created with BioRender.com.

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Funding

This study was supported by the National Key Research and Development Program of China (Grant No. 2018YFA0902803), National Natural Science Foundation of China (Grant No.81825016, 81961128027, and 81902586), Key Areas Research and Development Program of Guangdong (Grant No. 2018B010109006).

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Author notes

  1. These authors contributed equally: Yi Ouyang, Wenlong Zhong, Peiqi Xu, Bo Wang.

Authors and Affiliations

  1. Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiangxi Road, Guangzhou, Guangdong, 510120, China

    Yi Ouyang, Wenlong Zhong, Bo Wang, Junyu Chen, Longhao Xu, Ziwei Ou, Daqin Wu, Yi Lin, Jian Huang & Tianxin Lin

  2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China

    Yi Ouyang, Wenlong Zhong, Bo Wang, Junyu Chen, Longhao Xu, Ziwei Ou, Daqin Wu, Yi Lin, Jian Huang & Tianxin Lin

  3. Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, 510120, China

    Yi Ouyang, Wenlong Zhong, Bo Wang, Junyu Chen, Longhao Xu, Ziwei Ou, Daqin Wu, Yi Lin, Jian Huang & Tianxin Lin

  4. Department of Urology, Yan’ an Hospital, Kunming Medical University, 245 Renmin Dong Road, Kunming, Yunnan, 650051, China

    Peiqi Xu, Lin Zhang, Meng Yang & Chunhui Wang

  5. Department of Intensive Care, Ezhou Central Hospital, 9 Wenxing Road, Ezhou, Hubei, 436099, China

    Peiqi Xu

  6. BioMed Laboratory, Guangzhou Jingke Biotech Group, Guangzhou, Guangdong, 510320, China

    Hong Li & Sheng Li

  7. School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, China

    Xiang Chen

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  1. Yi Ouyang
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Contributions

Conceptualization: YO, WZ, PX, and MY. Methodology: YO, LX, PX, LZ, HL, SL, XC, and JC. Software: YO, and YL. Formal Analysis: YO, WZ, PX, and BW. Investigation: YO, WZ, PX, DW, and ZO. Writing: YO, WZ, PX, and BW. Writing, Review & Editing: YO, WZ, TL, and JH. Visualization: YO. Funding Acquisition: TL, JH, and WZ. Resources: TL, JH, and WZ. Supervision: TL, JH, and CW.

Corresponding authors

Correspondence to Wenlong Zhong, Chunhui Wang, Jian Huang or Tianxin Lin.

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All tissues and samples were obtained with written informed consent from patients involved. The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Sun Yat-sen Memorial Hospital (approval number: SYSKY-2023-422-01). Animal experiments were performed with the approval of the Institutional Animal Care and Use Committee (IACUC) of the SCUT (approval number: 2022006).

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Ouyang, Y., Zhong, W., Xu, P. et al. Tumor-associated neutrophils suppress CD8+ T cell immunity in urothelial bladder carcinoma through the COX-2/PGE2/IDO1 Axis. Br J Cancer 130, 880–891 (2024). https://doi.org/10.1038/s41416-023-02552-z

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