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

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

doi:10.3390/cancers12082045

レンバチニブという血管新生阻害剤または肝動脈化学塞栓術(TACE)で治療を受けた肝がん患者の血液で、16種類の可溶性免疫チェックポイント分子を測定したところ、治療導入の1週間後に早くも複数の分子の濃度が有意に変化していることを発見しました。この発見は、肝がんに対しては既存の治療法であっても、がん微小環境の免疫状態に影響を与えている可能性を示しています。肝がんは、日本で年間3万人近くが亡くなる重要な疾患であり、治療法について研究が進められています。がん免疫療法である免疫チェックポイント阻害剤は様々ながんで使われ効果をあげていますが、肝がんにおいては単剤での効果は認められていません。今回の研究成果より、肝がんに対しては免疫チェックポイント阻害剤に血管新生阻害剤またはTACEなどの既存治療を併用することで相乗効果が得られる可能性が期待されます。

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.

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

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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

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