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

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.

Soluble B7-CD28 Family Inhibitory Immune Checkpoint Proteins and Anti-Cancer Immunotherapy

“…Other newer costimulatory and coinhibitory molecules belonging to CD28-B7 family receptors are being discovered and investigated for their role in cancer immune evasion such as BTLA, B7-H3, B7-H4, and B7-H5, etcetera (11,14,22) (Figure 1). Of these, BTLA (also known as CD272) has shown some similarities with CTLA-4 and PD-1 in their regulatory effects on T cell activation and is the subject of intense investigations in recent times (11,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). BTLA recognizes HVEM (herpes virus entry mediator, TNFRSF14, CD270) as its ligand and their interactions have shown to inhibit T cell activation and proliferation (22)(23)(24)(25)(26)(27)(28).…”

“…BTLA is expressed on naïve as well as activated T cells which suggests it may regulate all phases of T cell activation as opposed to CTLA-4 (early naïve phase of T cell activation) and PD-1 (late effector phase) (22,27,28). Several cancers have shown up-regulation of BTLA and its blockade has displayed an enhanced immune response (29)(30)(31)(32)(33)(34)(35)(36)(37). Other newly discovered B7 ligands such as B7-H3, B7-H4 and B7-H5 have also shown to play inhibitory roles in T cell activation, and have demonstrated up-regulation in various cancers (12-14, 38, 39).…”

“…Soluble forms of these molecules can be detected in plasma of healthy individuals that are either produced by shedding of the membrane form or through alternative splicing (29)(30)(31)(32)(40)(41)(42)(43)(44) (Figure 2). Elevated plasma levels are reported in disease progression, autoimmune diseases and cancers (29-32, 39, 42).…”

“…In recent times, investigation into the soluble forms of these molecules have been exaggerated. Although, the bulk of the reports are aimed at assessing their predictive and prognostic value, studies have also reported that they are biologically active and could hold potential for anti-cancer therapy (29)(30)(31)(32)(40)(41)(42)(43)(44)(45). We will review these soluble inhibitory checkpoints in detail with a focus on their potential for anti-cancer immunotherapy.…”

Soluble Programmed Cell Death-1 Predicts Hepatocellular Carcinoma Development During Nucleoside Analogue Treatment

“…For values below the limit of detection, we used 10% of the lowest recorded value as a substitute. 19,41 In addition, of 13 patients who developed HCC during entecavir treatment, 9 had stored serum samples collected at 6 and 12 months after the start of entecavir treatment, at 6 and 12 months before HCC development, and at the time of HCC development, in which the sPD-1 level was measured via multiplexed uorescent bead-based immunoassay.…”