肿瘤细胞治疗研究
英文原题：The hepatic niche leads to aggressive natural killer cell leukemia proliferation through the transferrin-transferrin receptor 1 axis.
这些发现表明，肝脏作为成人中非经典的造血器官，是ANKL的主要生态位，而抑制Tf-TfR1轴是ANKL的一种有前景的治疗策略。
侵袭性NK 细胞白血病（ANKL）是一种罕见的淋巴系统肿瘤，常与Epstein-Barr病毒相关，预后极差。由于缺乏ANKL患者的样本及相关小鼠模型，对其发病机制包括肿瘤微环境（TME）的全面研究一直受到阻碍。在此，我们建立了3例来源于ANKL患者的异种移植小鼠模型（PDX），使得对肿瘤细胞及其TME的广泛分析成为可能。ANKL细胞主要在肝窦内定植和增殖。肝脏中的ANKL细胞以Myc通路富集为特征，且比其他器官中的ANKL细胞增殖更快。相互作用组分析和体内CRISPR-Cas9分析揭示转铁蛋白（Tf）-转铁蛋白受体1（TfR1）轴是肝脏与ANKL之间潜在的分子相互作用。ANKL细胞对铁剥夺相当敏感。PPMX-T003是一种人源化抗TfR1单克隆抗体，在使用ANKL-PDX的临床前研究中显示出显著的治疗效果。这些发现表明，肝脏——成人中非经典的造血器官——是ANKL的主要生态位，而抑制Tf-TfR1轴是ANKL的一种有前景的治疗策略。
Aggressive natural killer cell leukemia (ANKL) is a rare lymphoid neoplasm frequently associated with Epstein-Barr virus, with a disastrously poor prognosis. Owing to the lack of samples from patients with ANKL and relevant murine models, comprehensive investigation of its pathogenesis including the tumor microenvironment (TME) has been hindered. Here we established 3 xenograft mice derived from patients with ANKL (PDXs), which enabled extensive analysis of tumor cells and their TME. ANKL cells primarily engrafted and proliferated in the hepatic sinusoid. Hepatic ANKL cells were characterized by an enriched Myc-pathway and proliferated faster than those in other organs. Interactome analyses and in vivo CRISPR-Cas9 analyses revealed transferrin (Tf)-transferrin receptor 1 (TfR1) axis as a potential molecular interaction between the liver and ANKL. ANKL cells were rather vulnerable to iron deprivation. PPMX-T003, a humanized anti-TfR1 monoclonal antibody, showed remarkable therapeutic efficacy in a preclinical setting using ANKL-PDXs. These findings indicate that the liver, a noncanonical hematopoietic organ in adults, serves as a principal niche for ANKL and the inhibition of the Tf-TfR1 axis is a promising therapeutic strategy for ANKL.
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