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Molecular Diagnostics

TIGIT and PD-1 expression atlas predicts response to adjuvant chemotherapy and PD-L1 blockade in muscle-invasive bladder cancer

Abstract

Background

TIGIT and PD-1 are checkpoint receptors that could regulate the functional status of immune cells through independent pathways. However, the clinical significance of immune classification based on TIGIT and PD-1 expression remains unclear in muscle-invasive bladder cancer (MIBC).

Methods

Patients with MIBC from four independent cohorts were categorised into three clusters. Survival analysis conducted through Kaplan–Meier curves and Cox regression model. Immune contexture was measured by immunohistochemistry and CIBERSORT algorithm. Twenty-five fresh tumour tissue samples were utilised to evaluate functional state of CD8+ T cells by flow cytometry.

Results

Cluster I (TIGITlowPD-1low) contained widely poor immune infiltrates with higher FGFR3 mutation, Cluster II (TIGITlowPD-1high) exhibited a highly infiltrated contexture with increased cytolytic CD8+ T cells and had the best prognosis, Cluster III (TIGIThigh) presented a suppressive tumour microenvironment (TME) featured by exhausted CD8+ T cells and basal molecular subtype. Patients of Cluster III had the worst survival but could benefit more from adjuvant chemotherapy and anti-PD-L1 immunotherapy, and also presented limited FGFR3 signalling signature but activated immunotherapeutic and EGFR-associated pathway.

Conclusions

TIGIT/PD-1-based risk stratification with distinct immune and molecular features could be served as a predictor for systematic therapeutic response including adjuvant chemotherapy and immunotherapy in MIBC patients.

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Fig. 1: Stratification based on TIGIT and PD-1 expression could predict prognosis in MIBC patients.
Fig. 2: Predictive value of stratification based on TIGIT and PD-1 expression for ACT responsiveness.
Fig. 3: Characterisation of the immune microenvironment based on TIGIT and PD-1 expression.
Fig. 4: Stratification based on TIGIT and PD-1 expression correlated with molecular features and immunotherapeutic implication.

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Data availability

All data generated that are relevant to the results presented in this article are included in this article. Other data that were not relevant for the results presented here are available from the corresponding author Dr. Xu upon reasonable request.

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Acknowledgements

We thank Dr. Lingli Chen (Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China) and Dr. Yunyi Kong (Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China) for their excellent pathological technology help.

Funding

This study was funded by grants from National Natural Science Foundation of China (31770851, 81872082, 81972279, 82002670, 82103408), Shanghai Municipal Natural Science Foundation (19ZR1431800), Shanghai Sailing Program (18YF1404500, 21YF1407000), Shanghai Municipal Commission of Health and Family Planning Program (201840168) and Fudan University Shanghai Cancer Center for Outstanding Youth Scholars Foundation (YJYQ201802). All these study sponsors have no roles in the study design, in the collection, analysis and interpretation of data.

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Authors and Affiliations

Authors

Contributions

Z Liu, H Zeng, K Jin, Y Yu and R You for acquisition of data, analysis and interpretation of data, statistical analysis and drafting of the manuscript; H Zhang, C Liu, X Su, S Yan, Y Chang, L Liu and L Xu for technical and material support; J Xu, Y Zhu and Z Wang for study concept and design, analysis and interpretation of data, drafting of the manuscript, obtained funding and study supervision. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jiejie Xu, Yu Zhu or Zewei Wang.

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Ethics approval and consent to participate

This study was approved by the Clinical Research Ethics Committee of Zhongshan Hospital, Fudan University (No. B2015-030) and the Ethics Committee of Fudan University Shanghai Cancer Center (No. 050432-4-1212B). Written informed consent was obtained from each patient.

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Liu, Z., Zeng, H., Jin, K. et al. TIGIT and PD-1 expression atlas predicts response to adjuvant chemotherapy and PD-L1 blockade in muscle-invasive bladder cancer. Br J Cancer 126, 1310–1317 (2022). https://doi.org/10.1038/s41416-022-01703-y

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