肿瘤细胞治疗研究
英文原题：Cancer-driver-agnostic targeting of amplified surface proteins identifies MPZL1 for selective CAR-T cell therapy.
我们发现MPZL1（髓鞘蛋白零样1）在多种癌症类型的表面肿瘤细胞上大量表达，而在健康组织中基本缺失，提供了有利的治疗窗口；该基因在特定实体瘤类型中高达75%的患者中存在扩增。
多数癌症疗法以驱动肿瘤生长的基因改变为靶点，但许多驱动因素目前难以成药或较为罕见，限制了此类疗法的适用范围。本研究表明，编码细胞表面蛋白的扩增基因可提供丰富的靶点来源，且不依赖特定癌症驱动因素。研究发现，MPZL1（髓鞘蛋白零样蛋白1）在某些实体瘤类型中有高达75%的患者存在扩增；它在多种癌症的肿瘤细胞表面均有大量表达，而在健康组织中基本不表达，因此具有较理想的治疗窗。研究人员制备了靶向MPZL1胞外结构域的单克隆抗体，并据此构建嵌合抗原受体（CAR）-T细胞；这些细胞可在体外选择性清除MPZL1阳性的癌细胞。在人源异种移植模型、自发性肿瘤小鼠模型和患者来源组织外植体模型中，CAR-T细胞均表现出抗肿瘤活性。本研究确立了MPZL1作为CAR-T细胞可行靶点的潜力，并提出一种通用框架，可利用扩增的细胞表面受体作为适用范围广泛的治疗靶点。
Most cancer therapies target genetic alterations driving tumor growth, but many drivers are undruggable or rare, limiting their therapeutic reach. Here, we demonstrate that amplified genes encoding cell surface proteins provide a rich, cancer-driver-agnostic source of targets. We identify MPZL1 (myelin protein zero-like 1), amplified in up to 75% of patients with certain solid tumor types, as abundantly expressed on the surface tumor cells across diverse cancer types while being largely absent from healthy tissues, offering a favorable therapeutic window. We develop a monoclonal antibody targeting MPZL1's extracellular domain and engineer chimeric antigen receptor (CAR)-T cells that selectively eliminate MPZL1-positive cancer cells in vitro. These CAR-T cells exhibit antitumor activity in human xenograft, autochthonous mouse, and patient-derived tissue explant preclinical models. This work establishes MPZL1 as a viable CAR-T cell target and provides a generalizable framework for exploiting amplified cell surface receptors as broadly applicable therapeutic targets.
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