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BAP1-related signature predicts benefits from immunotherapy over VEGFR/mTOR inhibitors in ccRCC: a retrospective analysis of JAVELIN Renal 101 and checkmate-009/010/025 trials

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Background

In patients with advanced clear cell renal cell carcinoma, despite the undoubted benefits from immune checkpoint inhibitor (ICI)-based therapies over monotherapies of angiogenic/mTOR inhibitors in the intention-to-treat population, approximately a quarter of the patients can scarcely gain advantage from ICIs, prompting the search for predictive biomarkers for patient selection.

Methods

Clinical and multi-omic data of 2428 ccRCC patients were obtained from The Cancer Genome Atlas (TCGA, n = 537), JAVELIN Renal 101 (avelumab plus axitinib vs. sunitinib, n = 885), and CheckMate-009/010/025 (nivolumab vs. everolimus, n = 1006).

Results

BAP1 mutations were associated with large progression-free survival (PFS) benefits from ICI-based immunotherapies over sunitinib/everolimus (pooled estimate of interaction HR = 0.71, 95% CI 0.51–0.99, P = 0.045). Using the top 20 BAP1 mutation-associated differentially expressed genes (DEGs) generated from the TCGA cohort, we developed the BAP1-score, negatively correlated with angiogenesis and positively correlated with multiple immune-related signatures concerning immune cell infiltration, antigen presentation, B/T cell receptor, interleukin, programmed death-1, and interferon. A high BAP1-score indicated remarkable PFS benefits from ICI-based immunotherapies over angiogenic/mTOR inhibitors (avelumab plus axitinib vs. sunitinib: HR = 0.55, 95% CI 0.43–0.70, P < 0.001; nivolumab vs. everolimus: HR = 0.72, 95% CI 0.52–1.00, P = 0.045), while these benefits were negligible in the low BAP1-score subgroup (HR = 1.16 and 1.02, respectively).

Conclusion

In advanced ccRCCs, the BAP1-score is a biologically and clinically significant predictor of immune microenvironment and the clinical benefits from ICI-based immunotherapies over angiogenic/mTOR inhibitors, demonstrating its potential utility in optimizing the personalized therapeutic strategies in patients with advanced ccRCC.

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Data availability

The authors declare that relevant data supporting the findings of this study are available within the paper and its Supplementary files. The references of all the included datasets are shown in Supplementary Table 1. Due to ethical and privacy concerns, we are unable to publish their full data in our study. Readers could contact the corresponding authors for the access of individual patient-level data for non-commercial purposes.

Abbreviations

ccRCC:

Clear cell renal cell carcinoma

CI:

Confidence interval

CM-009/010/025:

Checkmate-009/010/025

CTLA-4:

Cytotoxic T-cell lymphocyte-4

DDR:

DNA damage repair

DEG:

Differentially expressed gene

GES:

Gene expression score

HR:

Hazard ratio

ICI:

Immune checkpoint inhibitor

IHC:

Immunohistochemical

PD-1:

Programmed cell death-1

PD-L1:

Programmed death-ligand 1

TCGA-KIRC:

The cancer genome atlas-kidney renal clear cell carcinoma

TKI:

Tyrosine kinase inhibitor

TMB:

Tumor mutational burden

TPM:

Transcripts per million,

RRR:

Ratio of relative risk

ssGSEA:

Single sample gene set enrichment analysis

STROBE:

Strengthening the reporting of observational studies in epidemiology

VEGFR:

Vascular endothelial growth factor receptor

WES:

Whole-exome sequencing

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Acknowledgements

We thank Dizai Shi (Stitch) for his emotional support and the researchers involved in the TCGA-KIRC dataset and the clinical trials (JAVELIN and CM-009/010/025) who shared patient-level data for public use.

Funding

This work was supported by National Natural Science Foundation of China (81770790 and 81972389 to Xu Zhang) and Hainan Province Science and Technology Special Fund (ZDYF2021SHFZ056 to Taoping Shi).

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Author notes

  1. Kan Liu and Yan Huang have contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, The Third Medical Center of PLA General Hospital, Yongding Road 69, Haidian District, Beijing, 100039, China

    Kan Liu, Yan Huang, Xu Zhang & Taoping Shi

  2. Burning Rock Biotech, Guangzhou, Guangdong, China

    Yu Xu, Guoqiang Wang & Shangli Cai

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  1. Kan Liu
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KL, YH, YX, and TS conceptualized and designed this study. KL and YX developed the methodology and acquired the data. KL, YH, YX, and TS analyzed and interpreted the data. All authors contributed to the writing, review, and/or revision of the manuscript. GW, SC, and XZ provided administrative, technical, and/or material support. XZ and TS supervised this study. All authors approved the submitted version of manuscript.

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Correspondence to Xu Zhang or Taoping Shi.

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The authors declare no potential conflicts of interest, except the employment of Yu Xu, Guoqiang Wang, and Shangli Cai in Burning Rock Biotech.

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Our study is following the principles of the Declaration of Helsinki and was approved by the Institution Review Board of Chinese PLA General Hospital (ChiCTR2000030405).

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Liu, K., Huang, Y., Xu, Y. et al. BAP1-related signature predicts benefits from immunotherapy over VEGFR/mTOR inhibitors in ccRCC: a retrospective analysis of JAVELIN Renal 101 and checkmate-009/010/025 trials. Cancer Immunol Immunother 72, 2557–2572 (2023). https://doi.org/10.1007/s00262-023-03424-4

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