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Analysis of the immunological markers BTLA, TIM-3, and PD-L1 at the invasion front and tumor center in clear cell renal cell carcinoma

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Abstract

Purpose

Immune checkpoint inhibitors (ICI) are then backbone in the therapy of metastatic renal cell carcinoma (RCC). The aim of this analysis was to explore the different expression of the ICI PD-L1, BTLA, and TIM-3 at the different tumor locations of the invasion front and the tumor center.

Methods

Large-area sections of the tumor center and invasion front of 44 stage pT1–4 clear cell RCCs were examined immunohistochemically using antibodies against BTLA, TIM-3, and PD-L1 and subsequently correlated with clinicopathologic data.

Results

TIM-3 was most strongly expressed at the invasion front (mean ± SD: 84.1 ± 46.6, p = 0.094). BTLA expression was highest in normal tissue, with weak staining in the tumor center and at the invasion front [110.2 vs. 18.6 (p < 0.001) vs. 32.2 (p = 0.248)]. PD-L1 was weakly expressed at the tumor center (n = 5/44) and at the invasion front (n = 5/44). Correlation with clinicopathological parameters revealed significantly higher BTLA expression in ≥ T3 tumors compared to T1/2 tumors (tumor center p = 0.009; invasion front p = 0.005). BTLA-positive tumors at the tumor center correlated with worse CSS (median 48.46 vs. 68.91 months, HR 4.43, p = 0.061). PD-L1 expression was associated with worse CSS (median 1.66 vs. 4.5 years, HR 1.63, p = 0.652). For TIM-3, there were no significant associations with clinicopathological parameters and survival.

Conclusion

The present results show heterogeneous intratumoral and intertumoral expression of the investigated checkpoint receptors PD-L1, BTLA, and TIM-3. In the clinical practice tumor sampling should include different tumor locations, and multiple inhibition of different checkpoint receptors seems reasonable to increase the therapeutic success.

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Funding

MS and ES were in part supported by the Robert Bosch Stiftung Stuttgart, Germany.

Author information

Authors and Affiliations

  1. Department of Urology, University Hospital Tuebingen, Eberhard-Karls-University Tuebingen, Tübingen, Germany

    Viktoria Stühler, Bilal Alemi, Steffen Rausch, Arnulf Stenzl & Jens Bedke

  2. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany

    Matthias Schwab & Elke Schaeffeler

  3. University of Tübingen, Tübingen, Germany

    Matthias Schwab & Elke Schaeffeler

  4. Departments of Clinical Pharmacology, Pharmacy and Biochemistry, University of Tuebingen, Tübingen, Germany

    Matthias Schwab

  5. Cluster of Excellence iFIT (EXC2180) ‘Image-Guided and Functionally Instructed Tumor Therapies’, Faculty of Medicine, University of Tübingen, Tübingen, Germany

    Matthias Schwab & Elke Schaeffeler

  6. German Cancer Consortium (DKTK), Partner Site Tübingen, 72076, Tübingen, Germany

    Matthias Schwab

  7. Department of Urology and Transplantation Surgery, Klinikum Stuttgart, Kriegsbergstraße 60, 70174, Stuttgart, Germany

    Jens Bedke

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Contributions

VS: Protocol/project development, Data collection or management, Data analysis, Manuscript writing; BA: Data collection or management, Data analysis; SR: Review & editing; AS: Review & editing, Supervision; MS: Review & editing, Supervision; ES: Review & editing; Supervision; JB: Protocol/project development, Review & editing, Project administration.

Corresponding author

Correspondence to Jens Bedke.

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Conflict of interest

JB reports institutional research grants as local principal investigator from BMS, Ipsen, MSD, Pfizer, Roche, Astellas, AstraZeneca, Eisai, Nektar, Novartis, Seagen; consulting fees from Apogepha, Astellas, AstraZeneca, BMS, Eisai, Ipsen, Janssen, Merck Serono, MSD, Pfizer, Roche, Speakers' bureau fees from Astellas, BMS, Ipsen, Merck Serono, MSD, Pfizer, Roche and Seagen; travel support from Merck and steering committee member for BMS, MSD, Pfizer and Seagen. SR: honoraria for speaker, advisory role: Astellas, Bayer, Pfizer, Merck. AS: consultancies, honoraria, or study participation from Bayer, BMS, Immatics, Novartis, Pfizer, and Roche. The remaining authors declare that they have no competing interests.

Ethical approval

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the University of Tuebingen (565/2020/BO).

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Informed consent was obtained from all subjects involved in the study.

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Stühler, V., Alemi, B., Rausch, S. et al. Analysis of the immunological markers BTLA, TIM-3, and PD-L1 at the invasion front and tumor center in clear cell renal cell carcinoma. World J Urol 42, 53 (2024). https://doi.org/10.1007/s00345-023-04721-4

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