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HLA class I expression predicts prognosis and therapeutic benefits from tyrosine kinase inhibitors in metastatic renal-cell carcinoma patients

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Abstract

Purpose

Classical HLA class I antigen is highly involved in antigen presentation and adaptive immune response against tumor. In this study, we explored its predictive value for treatment response and survival in metastatic renal-cell carcinoma (mRCC) patients.

Experimental design

A TKI cohort of 111 mRCC patients treated with sunitinib or sorafenib and a non-TKI cohort of 160 mRCC patients treated with interleukin-2 or interferon-α-based immunotherapy at a single institution were retrospectively enrolled. HLA class I expression and cytotoxic T lymphocyte (CTL) density was assessed by immunohistochemistry on tissue microarrays. Association between HLA class I and CTL was also assessed in the TCGA KIRC cohort.

Results

In the TKI cohort, down-regulated HLA class I was associated with lower objective response rate of TKI therapy (P = 0.004), shorter overall survival (OS) (P = 0.001), and shorter progression free survival (PFS) (P < 0.001). Multivariate Cox regression model defined HLA expression as an independent prognostic factor for both OS [hazard ratio 1.687 (95% CI 1.045–2.724), P = 0.032] and PFS [hazard ratio 2.139 (95% CI 1.376–3.326), P = 0.001]. In the non-TKI cohort, HLA class I was not significantly associated with survival. HLA class I expression was associated with CTL infiltration and function, and its prognostic value was more predominant in CTL high-density tumors (P < 0.001) rather than CTL low-density tumors (P = 0.294).

Conclusions

Classical HLA class I expression can serve as a potential predictive biomarker for TKI therapy in mRCC patients. Its predictive value was restricted in CTL high-density tumors. However, further external validations and functional investigations are still required.

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Abbreviations

IMDC:

International Metastatic Renal-Cell Carcinoma Database Consortium

KIRC:

Kidney renal clear cell carcinoma

mRCC:

Metastatic renal-cell carcinoma

RCC:

Renal-cell carcinoma

TCGA:

The Cancer Genome Atlas

TKI:

Tyrosine kinase inhibitor

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Acknowledgements

This study was funded by grants from National Natural Science Foundation of China (31270863, 81471621, 81472227, 81472376 and 81671628), Program for New Century Excellent Talents in University (NCET-13-0146), Shanghai Municipal Natural Science Foundation (14ZR1406300) and Zhongshan Hospital Science Foundation (2016ZSQN30). All these study sponsors have no roles in the study design, in the collection, analysis, and interpretation of data.

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Author notes

  1. Jiajun Wang, Li Liu, and Yang Qu contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200032, China

    Jiajun Wang, Li Liu, Yang Qu, Wei Xi, Yu Xia, Qi Bai, Ying Xiong, Qilai Long & Jianming Guo

  2. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, No. 138 Yixueyuan Road, Shanghai, 200032, China

    Jiejie Xu

Authors
  1. Jiajun Wang
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  2. Li Liu
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  4. Wei Xi
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  5. Yu Xia
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  6. Qi Bai
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  7. Ying Xiong
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Contributions

JX and JG conceived and designed the study. JW, LL, and YQ contributed to the acquisition, analysis, and interpretation of data. JW, LL, and YQ performed the statistical analysis. JW wrote the paper. JW, LL, YQ, JX, and JG reviewed and edited the manuscript. WX, YX, QB, YX, and QL provided technical and material support. JX and JG contributed to funding obtaining and study supervision. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Jiejie Xu or Jianming Guo.

Ethics declarations

Ethical approval

This study was approved by the institutional ethical review boards of Zhongshan Hospital, Fudan University (Registration No. B2015-030).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Conflict of interest

The authors declare that they have no conflict of interest.

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Wang, J., Liu, L., Qu, Y. et al. HLA class I expression predicts prognosis and therapeutic benefits from tyrosine kinase inhibitors in metastatic renal-cell carcinoma patients. Cancer Immunol Immunother 67, 79–87 (2018). https://doi.org/10.1007/s00262-017-2064-1

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  • DOI: https://doi.org/10.1007/s00262-017-2064-1

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