Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
Cell Mol Gastroenterol Hepatol. 2021;12(2):443-464. doi: 10.1016/j.jcmgh.2021.03.003. Epub 2021 Mar 27.
BACKGROUND & AIMS: TIGIT is a co-inhibitory receptor, and its suitability as a target for cancer immunotherapy in HCC is unknown. PD1 blockade is clinically effective in about 20% of advanced HCC patients. Here we aim to determine whether co-blockade of TIGIT/PD1 has added value to restore functionality of HCC tumor-infiltrating T cells (TILs).
Mononuclear leukocytes were isolated from tumors, paired tumor-free liver tissues (TFL) and peripheral blood of HCC patients, and used for flow cytometric phenotyping and functional assays. CD3/CD28 T-cell stimulation and antigen-specific assays were used to study the ex vivo effects of TIGIT/PD1 single or dual blockade on T-cell functions.
TIGIT was enriched, whereas its co-stimulatory counterpart CD226 was down-regulated on PD1 CD8 TILs. PD1 TIGIT CD8 TILs co-expressed exhaustion markers TIM3 and LAG3 and demonstrated higher TOX expression. Furthermore, this subset showed decreased capacity to produce IFN-γ and TNF-α. Expression of TIGIT-ligand CD155 was up-regulated on tumor cells compared with hepatocytes in TFL. Whereas single PD1 blockade preferentially enhanced ex vivo functions of CD8 TILs from tumors with PD1 CD8 TILs (high PD1 expressers), co-blockade of TIGIT and PD1 improved proliferation and cytokine production of CD8 TILs from tumors enriched for PD1 CD8 TILs (low PD1 expressers). Importantly, ex vivo co-blockade of TIGIT/PD1 improved proliferation, cytokine production, and cytotoxicity of CD8 TILs compared with single PD1 blockade.
Ex vivo, co-blockade of TIGIT/PD1 improves functionality of CD8 TILs that do not respond to single PD1 blockade. Therefore co-blockade of TIGIT/PD1 could be a promising immune therapeutic strategy for HCC patients.
TIGIT 是一种共抑制受体，其作为 HCC 癌症免疫治疗靶点的适用性尚不清楚。PD1 阻断在约 20%的晚期 HCC 患者中具有临床疗效。在此，我们旨在确定共阻断 TIGIT/PD1 是否能增加恢复 HCC 肿瘤浸润性 T 细胞（TIL）功能的价值。
从 HCC 患者的肿瘤、配对无肿瘤肝脏组织（TFL）和外周血中分离单核白细胞，用于流式细胞术表型分析和功能测定。使用 CD3/CD28 T 细胞刺激和抗原特异性测定来研究 TIGIT/PD1 单或双阻断对 T 细胞功能的体外作用。
PD1 TIGIT CD8 TIL 共表达衰竭标志物 TIM3 和 LAG3，并表现出更高的 TOX 表达，而 TIGIT 在 PD1 CD8 TIL 上富集，而其共刺激对应物 CD226 下调。此外，该亚群产生 IFN-γ 和 TNF-α 的能力下降。与 TFL 中的肝细胞相比，肿瘤细胞上表达的 TIGIT 配体 CD155 增加。虽然单独的 PD1 阻断优先增强具有 PD1 CD8 TIL 的肿瘤中 CD8 TIL 的体外功能（高 PD1 表达者），但 TIGIT 和 PD1 的共阻断改善了富含 PD1 CD8 TIL 的肿瘤中 CD8 TIL 的增殖和细胞因子产生（低 PD1 表达者）。重要的是，与单独的 PD1 阻断相比，体外共阻断 TIGIT/PD1 可改善 CD8 TIL 的增殖、细胞因子产生和细胞毒性。
体外共阻断 TIGIT/PD1 可改善对单独 PD1 阻断无反应的 CD8 TIL 的功能。因此，TIGIT/PD1 的共阻断可能是 HCC 患者有前途的免疫治疗策略。
