Department of Surgery, Weill Cornell Medicine, New York, New York.
Department of Radiology, Weill Cornell Medicine, New York, New York.
Clin Cancer Res. 2020 Nov 15;26(22):6003-6016. doi: 10.1158/1078-0432.CCR-20-1523. Epub 2020 Sep 4.
Advanced thyroid cancers, including poorly differentiated and anaplastic thyroid cancer (ATC), are lethal malignancies with limited treatment options. The majority of patients with ATC have responded poorly to programmed death 1 (PD1) blockade in early clinical trials. There is a need to explore new treatment options.
We examined the expression of PD-L1 (a ligand of PD1) and intercellular adhesion molecule 1 (ICAM1) in thyroid tumors and ATC cell lines, and investigated the PD1 expression level in peripheral T cells of patients with thyroid cancer. Next, we studied the tumor-targeting efficacy and T-cell dynamics of monotherapy and combination treatments of ICAM1-targeting chimeric antigen receptor (CAR) T cells and anti-PD1 antibody in a xenograft model of ATC.
Advanced thyroid cancers were associated with increased expression of both ICAM1 and PD-L1 in tumors, and elevated PD1 expression in CD8 T cells of circulating blood. The expression of ICAM1 and PD-L1 in ATC lines was regulated by the IFNγ-JAK2 signaling pathway. ICAM1-targeted CAR T cells, produced from either healthy donor or patient T cells, in combination with PD1 blockade demonstrated an improved ability to eradicate ICAM1-expressing target tumor cells compared with CAR T treatment alone. PD1 blockade facilitated clearance of PD-L1 high tumor colonies and curtailed excessive CAR T expansion, resulting in rapid tumor clearance and prolonged survival in a mouse model.
Targeting two IFNγ-inducible, tumor-associated antigens-ICAM1 and PD-L1-in a complementary manner might be an effective treatment strategy to control advanced thyroid cancers .
包括低分化和间变性甲状腺癌（ATC）在内的晚期甲状腺癌是致命的恶性肿瘤，治疗选择有限。大多数 ATC 患者在早期临床试验中对程序性死亡 1（PD1）阻断的反应不佳。因此，需要探索新的治疗选择。
我们检测了甲状腺肿瘤和 ATC 细胞系中 PD-L1（PD1 的配体）和细胞间黏附分子 1（ICAM1）的表达，并研究了甲状腺癌患者外周血 T 细胞中 PD1 的表达水平。接下来，我们研究了在 ATC 的异种移植模型中，ICAM1 靶向嵌合抗原受体（CAR）T 细胞和抗 PD1 抗体的单药治疗和联合治疗的肿瘤靶向疗效和 T 细胞动力学。
晚期甲状腺癌与肿瘤中 ICAM1 和 PD-L1 的表达增加以及循环血液中 CD8 T 细胞中 PD1 的表达升高相关。IFNγ-JAK2 信号通路调节 ATC 系中 ICAM1 和 PD-L1 的表达。来自健康供体或患者 T 细胞的 ICAM1 靶向 CAR T 细胞与 PD1 阻断联合治疗，与单独使用 CAR T 治疗相比，消灭表达 ICAM1 的靶肿瘤细胞的能力得到了提高。PD1 阻断促进了 PD-L1 高肿瘤集落的清除，并抑制了 CAR T 的过度扩增，从而在小鼠模型中快速清除肿瘤并延长了生存时间。
以互补的方式靶向两个 IFNγ诱导的肿瘤相关抗原-ICAM1 和 PD-L1，可能是控制晚期甲状腺癌的有效治疗策略。
