肿瘤细胞治疗研究
英文原题：Exploiting the CD200-CD200R immune checkpoint axis in multiple myeloma to enhance CAR T-cell therapy.
接受 B 细胞成熟抗原（BCMA）特异性嵌合抗原受体（CAR）T 细胞治疗的多发性骨髓瘤（MM）患者通常以 BCMA+ 疾病复发，提示存在 CAR-T 细胞抑制。
接受 B 细胞成熟抗原（BCMA）特异性嵌合抗原受体（CAR）T 细胞治疗的多发性骨髓瘤（MM）患者通常以 BCMA⁺ 疾病复发，提示 CAR-T 细胞受到抑制。CD200 是一种免疫检查点，在 MM 异常浆细胞（aPC）上过表达，并且是独立的不良生存预后因素；但 MM 细胞系不表达 CD200，这限制了当前临床前模型。研究人员对 MM 细胞系进行工程化改造，使其 CD200 表达水平达到 MM aPC 水平，并显示这一表达足以抑制临床阶段、靶向 BCMA 或 mucin 1 的 Tn 糖基化形式（TnMUC1）的 CAR-T 细胞；两类细胞分别由 4-1BB 和 CD2 提供共刺激。为阻止 CD200 介导的 CAR-T 抑制，研究比较了 CRISPR-Cas9 介导的 CD200 受体敲除（CD200RKO），以及共表达以下受体变体的策略：无信号功能的显性负性受体（CD200RDN），或利用 CD200 信号提供 CD28 共刺激的 CD200R-CD28 转换受体。结果发现，CD200R-CD28 转换受体显著增强 CAR-T 细胞的多功能性，并改善其细胞毒性、增殖能力、代谢和慢性抗原暴露条件下的表现。CD200RDN 带来了一定益处，但令人意外的是，CD200RKO 会损害 CAR-T 细胞活性，并对其代谢产生不利影响。在浆细胞瘤小鼠异种移植模型和播散性、以骨髓为主要受累部位的疾病模型中也观察到相同规律。本研究结果强调 CD200 介导的免疫抑制在 MM CAR-T 治疗中的重要性，并指出利用 aPC 上的 CD200 通过 CD200R-CD28 转换受体提供共刺激，是增强此类疗法的一种有前景的方法。
Patients with multiple myeloma (MM) treated with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells usually relapse with BCMA+ disease, indicative of CAR T-cell suppression. CD200 is an immune checkpoint that is overexpressed on aberrant plasma cells (aPCs) in MM and is an independent negative prognostic factor for survival. However, CD200 is not present on MM cell lines, a potential limitation of current preclinical models. We engineered MM cell lines to express CD200 at levels equivalent to those found on aPCs in MM and show that these are sufficient to suppress clinical-stage CAR T-cells targeting BCMA or the Tn glycoform of mucin 1 (TnMUC1), costimulated by 4-1BB and CD2, respectively. To prevent CD200-mediated suppression of CAR T cells, we compared CRISPR-Cas9-mediated knockout of the CD200 receptor (CD200RKO), to coexpression of versions of the CD200 receptor that were nonsignaling, that is, dominant negative (CD200RDN), or that leveraged the CD200 signal to provide CD28 costimulation (CD200R-CD28 switch). We found that the CD200R-CD28 switch potently enhanced the polyfunctionality of CAR T cells, and improved cytotoxicity, proliferative capacity, CAR T-cell metabolism, and performance in a chronic antigen exposure assay. CD200RDN provided modest benefits, but surprisingly, the CD200RKO was detrimental to CAR T-cell activity, adversely affecting CAR T-cell metabolism. These patterns held up in murine xenograft models of plasmacytoma, and disseminated bone marrow predominant disease. Our findings underscore the importance of CD200-mediated immune suppression in CAR T-cell therapy of MM, and highlight a promising approach to enhance such therapies by leveraging CD200 expression on aPCs to provide costimulation via a CD200R-CD28 switch.
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