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Checkpoint molecule PD-1-assisted CD8+ T lymphocyte count in tumor microenvironment predicts overall survival of patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors

Authors Yao J, Xi W, Zhu Y, Wang H, Hu X, Guo J

Received 23 April 2018

Accepted for publication 28 June 2018

Published 11 September 2018 Volume 2018:10 Pages 3419—3431

DOI https://doi.org/10.2147/CMAR.S172039

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 3

Editor who approved publication: Dr Antonella D'Anneo


Jiaxi Yao,* Wei Xi,* Yanjun Zhu, Hang Wang, Xiaoyi Hu, Jianming Guo

Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China

*These authors contributed equally to this work

Purpose: The aim of this study was to determine whether CD8+ T lymphocyte and its checkpoint-associated module programmed cell death protein 1 (PD-1)/main ligand of PD-1 (PD-L1) pathway impact overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKIs).
Materials and methods: A total of 231 mRCC patients, from 2007 to 2017, treated with sunitinib or sorafenib in Zhongshan Hospital, Fudan University were included in the study analyses. CD8, PD-1, and PD-L1 was assessed by immunohistochemistry on continuous paraffin-embedded slides. Kaplan–Meier method and COX regression model were applied in the survival analyses.
Results: Baseline characteristics were comparable between the training (n=118) and validation (n=113) sets. Patients with high CD8+ T lymphocytes infiltration and low PD-1 expression had longer survival in both sets (P=0.0106 and P=0.0047 in training set, P=0.0291 and P=0.0011 in validation set, respectively). However, survival stratified by PD-L1 was only insignificant or marginally significant. Multivariable analyses verified that CD8+ T lymphocytes, together with PD-1, but not tumor infiltrating mononuclear cells or tumor cells PD-L1, were independent prognostic factors (training set [HR 3.202, 95% CI 1.433–7.153, P=0.011] and validation set [HR 4.012, 95% CI 2.354–6.838, P<0.001]). Subsequent analysis revealed that the PD-1 high/CD8 low group had shorter survival (16 months) than PD-1 low/CD8 high group (51 months, P<0.0001). Combining the International Metastatic Renal Cancer Database Consortium system with the PD-1/CD8 model exhibited much better accuracy for the prediction of OS.
Conclusion: Our findings suggest that abundant CD8+ T cells are significantly associated with longer OS in mRCC patients treated with TKIs. The most influential checkpoint-associated molecule, PD-1, assisted CD8+ T cell-stratified patients and could be used as a better predictive and prognostic factor for the mRCC patients.

Keywords: metastatic renal cell carcinoma, tyrosine kinase inhibitors, immune checkpoint, prognostic factor

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