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

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 ( = 24) or TACE ( = 22) treatment. In lenvatinib-treated patients, plasma levels of sCD27 (soluble cluster of differentiation 27) decreased ( = 0.040) and levels of sCD40 ( = 0.014) and sTIM-3 ( < 0.001) were increased at Week 1, while levels of sCD27 ( < 0.001) were increased significantly at Weeks 2 through 4. At Week 1 of TACE, in addition to sCD27 ( = 0.028), sCD40 ( < 0.001), and sTIM-3 (soluble T-cell immunoglobulin and mucin domain-3) ( < 0.001), levels of sHVEM (soluble herpesvirus entry mediator) ( = 0.003), sTLR-2 (soluble Toll-like receptor 2) ( = 0.009), sCD80 ( = 0.036), sCTLA-4 (soluble cytotoxic T-lymphocyte antigen 4) ( = 0.005), sGITR (soluble glucocorticoid-induced tumor necrosis factor receptor) ( = 0.030), sGITRL (soluble glucocorticoid-induced TNFR-related ligand) ( = 0.090), and sPD-L1 (soluble programmed death-ligand 1) ( = 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.