キタハラ　シユウジ   Kitahara Shiyuuji   北原　秀治    所属   医学研究科 医学研究科 (医学部医学科をご参照ください)    職種   特任准教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Dual PD-1 and VEGFR-2 blockade promotes vascular normalization and enhances anti-tumor immune responses in HCC.
掲載誌名	正式名：Hepatology (Baltimore, Md.) 略　 称：Hepatology ISSNコード：(1527-3350)0270-9139(Linking)
掲載区分	国外
巻・号・頁	pp.0
著者・共著者	Shigeta Kohei, Datta Meenal, Hato Tai, Kitahara Shuji, Chen Ivy X, Matsui Aya, Kikuchi Hiroto, Mamessier Emilie, Aoki Shuichi, Ramjiawan Rakesh R, Ochiai Hiroki, Bardeesy Nabeel, Huang Peigen, Jain Rakesh K, Cobbold Mark, Zhu Andrew X, Duda Dan G
担当区分	筆頭著者
発行年月	2019/08
概要	Activation of anti-tumor immune response using programmed death receptor-1 (PD-1) blockade showed benefit only in a fraction of hepatocellular carcinoma (HCC) patients. Combining PD-1 blockade with antiangiogenesis has shown promise in substantially increasing the fraction of HCC patients who respond to treatment, but the mechanism of this interaction is unknown. We recapitulated these clinical outcomes using orthotopic-grafted or induced-murine models of HCC. Specific blockade of vascular endothelial receptor 2 (VEGFR-2) using a murine antibody significantly delayed primary tumor growth but failed to prolong survival, while anti-PD-1 antibody treatment alone conferred a minor survival advantage in one model. However, dual anti-PD-1/VEGFR-2 therapy significantly inhibited primary tumor growth and doubled survival in both models. Combination therapy reprogrammed the immune microenvironment by increasing CD8+ cytotoxic T cell infiltration and activation, shifting the M1/M2 ratio of tumor-associated macrophages and reducing T regulatory cell (Treg) and CCR2+ monocyte infiltration in HCC tissue. In these models, VEGFR-2 was selectively expressed in tumor endothelial cells. Using spheroid cultures of HCC tissue, we found that PD-L1 expression in HCC cells was induced in a paracrine manner upon anti-VEGFR-2 blockade in endothelial cells in part via interferon-gamma expression. Moreover, we found that VEGFR-2 blockade increased the PD-1 expression in tumor-infiltrating CD4+ cells. We also found that under anti-PD-1 therapy, CD4+ cells promote normalized vessel formation in the face of antiangiogenic therapy with anti-VEGFR-2 antibody. CONCLUSION: We show that dual anti-PD-1/VEGFR-2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase overall survival in both anti-PD-1 therapy resistant and responsive HCC models. This article is protected by copyright. All rights reserved.
DOI	10.1002/hep.30889
PMID	31378984