Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Mol Immunol. 2012 Jul;51(3-4):263-72. doi: 10.1016/j.molimm.2012.03.023. Epub 2012 Apr 11.
Tumors exploit immunoregulatory checkpoints that serve to attenuate T cell responses as a means of circumventing immunologic rejection. Programmed death ligand 1 (PD-L1) is a negative regulator of T cell function and is frequently expressed by solid tumors. By engaging programmed death 1 (PD-1) on activated T cells, PD-L1(+) tumors directly render tumor-specific T cells, including adoptively transferred T cells, functionally exhausted. As a strategy to overcome tumor PD-L1 effects on adoptively transferred T cells, we sought to convert PD-1 to a T cell costimulatory receptor by exchanging its transmembrane and cytoplasmic tail with that of CD28. Rather than becoming exhausted upon engagement of PD-L1(+) tumors, we hypothesized that CD8(+) cytotoxic T lymphocytes (CTL) genetically modified to express this PD1:CD28 chimera would exhibit enhanced functional attributes. Here we show that cell surface expressed PD1:CD28 retains the capacity to bind PD-L1 resulting in T cell costimulation as evidenced by increased levels of ERK phosphorylation, augmentation of cytokine secretion, increased proliferative capacity, and enhanced expression of effector molecule Granzyme B. We provide evidence that this chimera could serve as a novel engineering strategy to overcome PD-L1 mediated immunosuppression.
肿瘤利用免疫调节检查点来削弱 T 细胞的反应，以此来逃避免疫排斥。程序性死亡配体 1（PD-L1）是 T 细胞功能的负调节剂，经常在实体瘤中表达。通过与激活的 T 细胞上的程序性死亡受体 1（PD-1）结合，PD-L1（+）肿瘤直接使肿瘤特异性 T 细胞，包括过继转移的 T 细胞，功能衰竭。为了克服肿瘤 PD-L1 对过继转移的 T 细胞的影响，我们试图通过将其跨膜和胞质尾区与 CD28 的尾区交换，将 PD-1 转化为 T 细胞共刺激受体。我们假设，与表达这种 PD1:CD28 嵌合体的 CD8(+)细胞毒性 T 淋巴细胞（CTL）相比，与 PD-L1（+）肿瘤结合后不会发生衰竭，而是会表现出增强的功能特性。在这里，我们表明，表面表达的 PD1:CD28 保留了与 PD-L1 结合的能力，从而导致 T 细胞共刺激，这表现在 ERK 磷酸化水平增加、细胞因子分泌增强、增殖能力增强以及效应分子颗粒酶 B 的表达增强。我们提供的证据表明，这种嵌合体可以作为一种新的工程策略来克服 PD-L1 介导的免疫抑制。
