Anti-PD-1 antibody armored γδ T cells enhance anti-tumor efficacy in ovarian cancer.
Anti-PD-1 antibody armored γδ T cells enhance anti-tumor efficacy in ovarian cancer.
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抗PD-1抗体装甲γδT细胞增强了卵巢癌的抗肿瘤功效。
DOI：
10.1038/s41392-023-01646-7
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发表时间：
2023-10-20
影响因子：
39.3
通讯作者：
Zhang, Jianmin
中科院分区：
文献类型：
--
作者：
Wang, Yue;Han, Jingyi;Wang, Dongdong;Cai, Menghua;Xu, Yi;Hu, Yu;Chen, Hui;He, Wei;Zhang, Jianmin
γδ T细胞具有独特的能力，可以检测各种低突变负荷的肿瘤，使其成为CAR-T细胞疗法的有吸引力的候选者。与αβ T细胞和其他免疫细胞不同，γδ T细胞在MHC非限制性、选择性细胞募集和快速激活方面更上级。然而，临床试验显示出有限的临床益处，并且γδ T细胞的过继移植常常达不到预期。我们假设γδ T细胞在根除肿瘤细胞方面的有限有效性可能归因于抑制性PD-1/PD-L1轴诱导的抑制性肿瘤微环境。本文中，我们构建了能够分泌人源化抗PD-1抗体的新型装甲γδ T细胞，称为“Lv-PD 1-γδ T细胞"。Lv-PD 1-γδ T细胞显示出改善的增殖和增强的对肿瘤细胞的细胞毒性，从而在卵巢肿瘤荷瘤小鼠中产生增强的治疗效果和存活益处。这些工程化的细胞表现出超过29天的延长的体内存活，在免疫缺陷NOD/SCID/γ裸小鼠中没有任何致瘤性的潜力。我们还发现Lv-PD 1-γδ T细胞在人源化NOD/SCID/γ裸小鼠中表现出优异的耐受性和安全性。通过在肿瘤中局部分泌抗PD 1抗体来减弱或消除免疫抑制并使细胞毒性功效最大化，Lv-PD 1-γδ T细胞可以用作有希望的针对癌症的“现成”细胞疗法。
γδ T cells have the unique ability to detect a wide range of tumors with low mutation burdens, making them attractive candidates for CAR-T-cell therapy. Unlike αβ T cells and other immune cells, γδ T cells are superior in MHC non-restriction, selective cell recruitment, and rapid activation. However, clinical trials have shown limited clinical benefits, and the adoptive transplantation of γδ T cells has often fallen short of expectations. We hypothesized that the limited effectiveness of γδ T cells in eradicating tumor cells may be attributed to the inhibitory tumor microenvironment induced by the suppressive PD-1/PD-L1 axis. Herein, we constructed novel armored γδ T cells capable of secreting humanized anti-PD-1 antibodies, referred to as “Lv-PD1-γδ T cells. Lv-PD1-γδ T cells showed improved proliferation and enhanced cytotoxicity against tumor cells, resulting in augmented therapeutic effects and survival benefits in ovarian tumor-bearing mice. These engineered cells demonstrated a prolonged in vivo survival of more than 29 days, without any potential for tumorigenicity in immunodeficient NOD/SCID/γ null mice. We also found that Lv-PD1-γδ T cells exhibited excellent tolerance and safety in humanized NOD/SCID/γ null mice. With attenuated or eliminated immunosuppression and maximized cytotoxicity efficacy by the local secretion of anti-PD1 antibodies in tumors, Lv-PD1-γδ T cells can serve as a promising “off-the-shelf” cell therapy against cancers.
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PD-1和PD-L1检查点信号传导抑制癌症免疫疗法：机制，组合和临床结果。
影响因子：
5.6
作者：
Alsaab HO;Sau S;Alzhrani R;Tatiparti K;Bhise K;Kashaw SK;Iyer AK
通讯作者：
Iyer AK
影响因子：
10.9
作者：
Park JA;Santich BH;Xu H;Lum LG;Cheung NV
通讯作者：
Cheung NV
DOI：
10.1007/978-3-030-49270-0_5
发表时间：
2020-01-01
期刊：
TUMOR MICROENVIRONMENT: HEMATOPOIETIC CELLS, PT B
影响因子：
--
作者：
Imbert, Caroline;Olive, Daniel
通讯作者：
Olive, Daniel
影响因子：
4.7
作者：
Castella B;Melaccio A;Foglietta M;Riganti C;Massaia M
通讯作者：
Massaia M
影响因子：
64.8
作者：
Burr ML;Sparbier CE;Chan YC;Williamson JC;Woods K;Beavis PA;Lam EYN;Henderson MA;Bell CC;Stolzenburg S;Gilan O;Bloor S;Noori T;Morgens DW;Bassik MC;Neeson PJ;Behren A;Darcy PK;Dawson SJ;Voskoboinik I;Trapani JA;Cebon J;Lehner PJ;Dawson MA
通讯作者：
Dawson MA