Department of Immunology, CAMS Key Laboratory of T-cell and Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Common Mechanism Research for Major Diseases, Beijing, 100005, China.
Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
Signal Transduct Target Ther. 2023 Oct 20;8(1):399. doi: 10.1038/s41392-023-01646-7.
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.
γδ T 细胞具有检测具有低突变负担的广泛肿瘤的独特能力,使其成为 CAR-T 细胞治疗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、选择性细胞募集和快速激活方面具有优势。然而,临床试验表明其临床获益有限,γδ T 细胞的过继移植常常达不到预期效果。我们假设 γδ T 细胞在消灭肿瘤细胞方面的有限效果可能归因于抑制性 PD-1/PD-L1 轴诱导的抑制性肿瘤微环境。在此,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-PD1-γδ T 细胞”。Lv-PD1-γδ T 细胞表现出改善的增殖能力和增强的对肿瘤细胞的细胞毒性,从而增强了卵巢荷瘤小鼠的治疗效果和生存获益。这些工程细胞在免疫缺陷 NOD/SCID/γ 缺陷小鼠体内的存活时间超过 29 天,没有任何致瘤性的潜在风险。我们还发现,Lv-PD1-γδ T 细胞在人源化 NOD/SCID/γ 缺陷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 抗体减轻或消除免疫抑制作用并最大限度地提高细胞毒性效果,Lv-PD1-γδ T 细胞可以作为一种有前途的“现成”细胞疗法来治疗癌症。
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