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

Abstract

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