肿瘤细胞治疗研究
英文原题：Successful targeting of PD-1/PD-L1 with chimeric antigen receptor-natural killer cells and nivolumab in a humanized mouse cancer model.
我们的研究突显了一个强大的平台，用于开发和评估先前未探索的治疗方案抗肿瘤疗效和安全性。
近几十年来，嵌合抗原受体（CAR）工程化免疫效应细胞已展现出有前景的抗白血病活性。然而，其在实体瘤中的疗效仍不令人满意，可能归因于肿瘤微环境（TME）的影响。在一个具有人源化免疫系统的新型小鼠癌症模型中，发现了肿瘤浸润性免疫抑制白细胞和耗竭的程序性死亡蛋白-1（PD-1）高表达T细胞，这更好地模拟了患者的TME，从而能够筛选和评估免疫治疗药物。特别是，肿瘤细胞表面的膜结合型程序性死亡配体1（PD-L1）水平升高，这成为自然杀伤（NK）细胞介导治疗的一个有吸引力的靶点。靶向PD-L1的造血干细胞来源CAR-NK（CAR pNK）细胞在体外和体内均显示出增强的抗实体瘤功能。CAR pNK细胞与nivolumab产生了协同抗实体瘤反应。总之，我们的研究突显了一个强大的平台，用于开发和评估先前未探索的治疗方案的抗肿瘤疗效和安全性。
In recent decades, chimeric antigen receptor (CAR)-engineered immune effector cells have demonstrated promising antileukemic activity. Nevertheless, their efficacy remains unsatisfactory on solid cancers, plausibly due to the influence of tumor microenvironments (TME). In a novel mouse cancer model with a humanized immune system, tumor-infiltrating immunosuppressive leukocytes and exhausted programmed death protein-1 (PD-1) high T cells were found, which better mimic patient TME, allowing the screening and assessment of immune therapeutics. Particularly, membrane-bound programmed death ligand 1 (PD-L1) level was elevated on a tumor cell surface, which serves as an attractive target for natural killer (NK) cell-mediated therapy. Hematopoietic stem cell-derived CAR-NK (CAR pNK) cells targeting the PD-L1 showed enhanced in vitro and in vivo anti-solid tumor function. The CAR pNK cells and nivolumab resulted in a synergistic anti-solid tumor response. Together, our study highlights a robust platform to develop and evaluate the antitumor efficacy and safety of previously unexplored therapeutic regimens.
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