PD1 Blockade Enhances ICAM1-Directed CAR T Therapeutic Efficacy in Advanced Thyroid Cancer.
PD1 Blockade Enhances ICAM1-Directed CAR T Therapeutic Efficacy in Advanced Thyroid Cancer.
复制标题
PD1阻断可增强ICAM1导向的CAR T治疗晚期甲状腺癌的疗效。
DOI：
10.1158/1078-0432.ccr-20-1523
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发表时间：
2020-11-15
期刊：
影响因子：
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通讯作者：
Min IM
中科院分区：
文献类型：
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作者：
Gray KD;McCloskey JE;Vedvyas Y;Kalloo OR;Eshaky SE;Yang Y;Shevlin E;Zaman M;Ullmann TM;Liang H;Stefanova D;Christos PJ;Scognamiglio T;Tassler AB;Zarnegar R;Fahey TJ 3rd;Jin MM;Min IM
晚期甲状腺癌，包括低分化和间变性甲状腺癌（ATC），是治疗选择有限的致命恶性肿瘤。在早期临床试验中，大多数ATC患者对程序性死亡1（PD 1）阻断反应较差。有必要探索新的治疗方案。我们检测了PD-L1（PD 1的配体）和细胞间粘附分子1（ICAM 1）在甲状腺肿瘤和ATC细胞系中的表达，并研究了甲状腺癌患者外周血T细胞中PD 1的表达水平。接下来，我们研究了ATC异种移植模型中靶向ICAM 1的CAR T细胞和抗PD 1抗体的单一和组合治疗的肿瘤靶向功效和T细胞动力学。晚期甲状腺癌与肿瘤中ICAM 1和PD-L1的表达增加以及循环血液中CD 8 + T细胞中PD 1表达升高相关。ATC细胞ICAM 1和PD-L1的表达受IFNγ-JAK 2信号通路的调节。从健康供体或患者T细胞产生的ICAM 1靶向CAR T细胞与PD 1阻断剂组合显示出与单独CAR T治疗相比根除表达ICAM 1的靶肿瘤细胞的能力提高。PD 1阻断促进了PD-L1高肿瘤集落的清除，并减少了过度的CAR T扩增，导致小鼠模型中的肿瘤快速清除和存活期延长。以互补的方式靶向两种IFNγ诱导的肿瘤相关抗原-ICAM 1和PD-L1 -可能是控制体内晚期甲状腺癌的有效治疗策略。
Advanced thyroid cancers, including poorly differentiated and anaplastic thyroid cancer (ATC), are lethal malignancies with limited treatment options. The majority of ATC patients 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 thyroid cancer patients. Next, we studied the tumor targeting efficacy and T cell dynamics of mono- and combination treatments of ICAM1-targeting 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 to 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 in vivo.