Early Change in the Plasma Levels of Circulating Soluble Immune Checkpoint Proteins in Patients with Unresectable Hepatocellular Carcinoma Treated by Lenvatinib or Transcatheter Arterial Chemoembolization.

Naoshi Odagiri,Sawako Uchida-Kobayashi,Masaru Enomoto,Akihiro Tamori,Maito Suoh,Kohei Kotani,Norifumi Kawada,Atsushi Hagihara,Minh Phuong Dong,Le Thi Thanh Thuy,Hoang Hai

doi:10.3390/cancers12082045

Abstract

Immune checkpoint inhibitors, combined with anti-angiogenic agents or locoregional treatments (e.g., transarterial chemoembolization (TACE)), are expected to become standard-of-care for unresectable hepatocellular carcinoma (HCC). We measured the plasma levels of 16 soluble checkpoint proteins using multiplexed fluorescent bead-based immunoassays in patients with HCC who underwent lenvatinib (n = 24) or TACE (n = 22) treatment. In lenvatinib-treated patients, plasma levels of sCD27 (soluble cluster of differentiation 27) decreased (p = 0.040) and levels of sCD40 (p = 0.014) and sTIM-3 (p < 0.001) were increased at Week 1, while levels of sCD27 (p < 0.001) were increased significantly at Weeks 2 through 4. At Week 1 of TACE, in addition to sCD27 (p = 0.028), sCD40 (p < 0.001), and sTIM-3 (soluble T-cell immunoglobulin and mucin domain–3) (p < 0.001), levels of sHVEM (soluble herpesvirus entry mediator) (p = 0.003), sTLR-2 (soluble Toll-like receptor 2) (p = 0.009), sCD80 (p = 0.036), sCTLA-4 (soluble cytotoxic T-lymphocyte antigen 4) (p = 0.005), sGITR (soluble glucocorticoid-induced tumor necrosis factor receptor) (p = 0.030), sGITRL (soluble glucocorticoid-induced TNFR-related ligand) (p = 0.090), and sPD-L1 (soluble programmed death-ligand 1) (p = 0.070) also increased. The fold-changes in soluble checkpoint receptors and their ligands, including sCTLA-4 with sCD80/sCD86 and sPD-1 (soluble programmed cell death domain–1) with sPD-L1 were positively correlated in both the lenvatinib and TACE treatment groups. Our results suggest that there are some limited differences in immunomodulatory effects between anti-angiogenic agents and TACE. Further studies from multicenters may help to identify an effective combination therapy.

Highlights

Primary liver cancer, of which hepatocellular carcinoma (HCC) is the most common type, is the third most common cause of cancer-related deaths worldwide [1,2]
Cancers 2020, 12, 2045 therapies, the two anti-angiogenic tyrosine kinase inhibitors sorafenib [6] and lenvatinib [7] are used as first-line treatments for patients with advanced-stage HCC
Some patients in the transarterial chemoembolization (TACE) group underwent the therapy as their initial HCC treatment, but none in the lenvatinib group (36.4% vs. 0%; p = 0.001)

Summary

Introduction

Of which hepatocellular carcinoma (HCC) is the most common type, is the third most common cause of cancer-related deaths worldwide [1,2]. Cancers 2020, 12, 2045 therapies, the two anti-angiogenic tyrosine kinase inhibitors sorafenib [6] and lenvatinib [7] are used as first-line treatments for patients with advanced-stage HCC. (programmed cell death domain–1) pembrolizumab [11], nivolumab [12] or nivolumab combined with anti–CTLA-4 (cytotoxic T-lymphocyte antigen 4) (ipilimumab) therapy [13], may be indicated for sorafenib-refractory patients [14,15,16]. Current clinical trials are focusing on whether combinations of different types of treatments, including anti-angiogenic agents and TACE, may be promising for the enhancement of the antitumor effects of immune checkpoint inhibitors [17]. Tremelimumab, an anti–CTLA-4 therapy, was more effective when paired with TACE than as monotherapy [20]

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