细胞毒性T细胞
CD8型
免疫疗法
医学
嵌合抗原受体
肿瘤微环境
体内
T细胞
PI3K/AKT/mTOR通路
免疫学
免疫系统
癌症研究
体外
生物
信号转导
细胞生物学
生物化学
生物技术
作者
Qunfang Zhang,Fang Zheng,Yuchao Chen,Chun-Ling Liang,Huazhen Liu,Feifei Qiu,Yunshan Liu,Hongfeng Huang,Weihui Lu,Zhenhua Dai
出处
期刊:Cancer immunology research
[American Association for Cancer Research]
日期:2024-02-26
卷期号:12 (5): 631-643
被引量:1
标识
DOI:10.1158/2326-6066.cir-23-0587
摘要
Abstract Chimeric antigen receptor (CAR) T cells are emerging as an effective antitumoral therapy. However, their therapeutic effects on solid tumors are limited because of their short survival time and the immunosuppressive tumor microenvironment. Memory T cells respond more vigorously and persist longer than their naïve/effector counterparts. Therefore, promoting CAR T-cell development into memory T cells could further enhance their antitumoral effects. HI-TOPK-032 is a T-LAK cell–originated protein kinase (TOPK)-specific inhibitor that moderately represses some types of tumors. However, it is unknown whether HI-TOPK-032 works on hepatocellular carcinoma (HCC) and whether it impacts antitumoral immunity. Using both subcutaneous and orthotopic xenograft tumor models of two human HCC cell lines, Huh-7 and HepG2, we found that HI-TOPK-032 significantly improved proliferation/persistence of CD8+ CAR T cells, as evidenced by an increase in CAR T-cell counts or frequency of Ki-67+CD8+ cells and a decrease in PD-1+LAG-3+TIM-3+CD8+ CAR T cells in vivo. Although HI-TOPK-032 did not significantly suppress HCC growth, it enhanced the capacity of CAR T cells to inhibit tumor growth. Moreover, HI-TOPK-032 augmented central memory CD8+ T cell (TCM) frequency while increasing eomesodermin expression in CD8+ CAR T cells in tumor-bearing mice. Moreover, it augmented CD8+ CAR TCM cells in vitro and reduced their expression of immune checkpoint molecules. Finally, HI-TOPK-032 inhibited mTOR activation in CAR T cells in vitro and in tumors, whereas overactivation of mTOR reversed the effects of HI-TOPK-032 on CD8+ TCM cells and tumor growth. Thus, our studies have revealed mechanisms underlying the antitumoral effects of HI-TOPK-032 while advancing CAR T-cell immunotherapy.
科研通智能强力驱动
Strongly Powered by AbleSci AI