Lenvatinib recruits cytotoxic GZMK+CD8 T cells in hepatocellular carcinoma
Tomoharu Yamada, Naoto Fujiwara, Naoto Kubota, Yuki Matsushita, T. Nakatsuka, Shigeyuki Kurosaki, Tatsuya Minami, Ryosuke Tateishi, Akihiko Ichida, Junichi Arita, Kiyoshi Hasegawa, Kazuhiko Koike, Mitsuhiro Fujishiro, Hayato Nakagawa
Abstract
BACKGROUND: Lenvatinib was expected to enhance the effect of immune checkpoint inhibitors (ICIs) for unresectable HCC; however, their combination therapy failed to show the synergy in the phase III clinical trial. METHODS: To elucidate lenvatinib-induced molecular modulation, we performed bulk RNA-sequencing and digital spatial profiling of 5 surgically resected human HCC specimens after lenvatinib treatment and 10 matched controls without any preceding therapy. FINDINGS: Besides its direct antitumor effects, lenvatinib recruited cytotoxic GZMK+CD8 T cells in intratumor stroma by CXCL9 from tumor-associated macrophages, suggesting that lenvatinib-treated HCC is in the so-called excluded condition that can diminish ICI efficacy.