PD-L1 expression on circulating tumor cells can be a predictive biomarker to PD-1 inhibitors combined with radiotherapy and antiangiogenic therapy in advanced hepatocellular carcinoma

Abstract

Aim: A programmed death 1 (PD-1) inhibitor coupled with radiotherapy and antiangiogenic therapy is a potential therapeutic strategy for advanced hepatocellular carcinoma (HCC). We aimed to determine if circulating tumor cells (CTCs) positive for programmed death-ligand 1 (PD-L1) could be employed as a predictive biomarker in HCC patients receiving triple therapy.

Methods: In this study, HCC patients received a PD-1 inhibitor in combination with intensity-modulated radiotherapy (IMRT) and antiangiogenic therapy. Following IMRT, the PD-1 inhibitor was administrated once every 3 weeks, while the antiangiogenic drug was given once a day. Treatment was continued until the disease progressed. Two mL of peripheral blood was collected at baseline, 1 month, and 3 months after treatment for CTC enrichment using the CytoSorter® system with a CytoSorter™ CTC PD-L1 Kit (Watson Biotech., China).

Result: A total of 47 HCC patients receiving the triple therapy were enrolled in this study. Patients with < 2 PD-L1+ CTCs at baseline had a higher objective response rate (ORR) and longer overall survival (OS) than those with ≥ 2 PD-L1+ CTCs (56.5% vs. 16.7%, p = 0.007; not reach vs. 10.8 months, p = 0.001, respectively). The count of PD-L1+ CTCs was found to be an independent predictive biomarker of OS. Furthermore, the objective response was more likely to be achieved in patients with a dynamic decrease in PD-L1+ CTC counts at 1 month after treatment.

Conclusions: Our study demonstrated that PD-L1+ CTCs could be a predictive biomarker for HCC patients receiving PD-1 inhibitors in combination with IMRT and antiangiogenic therapy.

Keywords: antiangiogenic therapy; circulating tumor cells; hepatocellular carcinoma; programmed death 1 inhibitor; programmed death-ligand 1; radiotherapy.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Su, Guo, He, Rao, Zhang, Yang, Huang, Gu, Xu, Liu, Wang, Chen, Wu, Hu, Zeng, Li, Tong, Li, Yang, Liu, Xu, Tan, Tang, Feng, Chen, Yang, Jin, Zhu, Li and Han.

Figures

Figure 1

Detection of CTCs and PD-L1+ CTCs. The counts of CTCs (blue bars) and PD-L1+ CTCs (red bars) per patient detected are presented at baseline. Nonresponders and responders were divided into two groups. PD-L1, programmed death-ligand 1; CTCs, circulating tumor cells.

Figure 2

Comparison of the number of CTCs (A) and PD-L1+ CTCs (B) between the nonresponse group and response group. (C) ROC curve was adopted to investigate the predictive value of PD-L1+ CTC counts. When applying a cut-off of 2 PD-L1+ CTCs, a specificity of 65.5%, a sensitivity of 76.5%, and an AUC of 0.710 were observed. R, responder; CTCs, circulating tumor cells; PD-L1, programmed death-ligand 1; ROC, receiver operating characteristic; CI, confidence interval; AUC, area under the curve.

Figure 3

Kaplan–Meier plots: (A) progression-free survival and (B) overall survival based on PD-L1 expression on CTCs at baseline. HR, hazard ratio; CI, confidence interval; CTCs, circulating tumor cells; PD-L1, programmed death-ligand 1.

Figure 4

Multivariate Cox regression analysis of progression-free survival and overall survival. HR, hazard ratio; CI, confidence interval; AFP, alpha fetoprotein; PD-L1, programmed death-ligand 1; CTCs, circulating tumor cells.

Figure 5

Changes in total CTC counts, PD-L1+ CTC counts and proportion of PD-L1+ CTC counts at baseline (T0), 1 months (T1), and 3 months (T2) after the beginning of triple therapy. (A) CTC counts in total enrolled patients. (B) PD-L1+ CTC counts in total enrolled patients. (C) PD-L1+ CTC counts in responders. (D) PD-L1+ CTC counts in nonresponders. PD-L1, programmed death-ligand 1; CTCs, circulating tumor cells.