从论文中学习英语，用到自己的文章中，今天带来的文章题目为《将CAR - T细胞引入实体瘤》。
Steering CAR T Cells into Solid Tumors
Brown MH, Dustin ML. Steering CAR T Cells into Solid Tumors. New England Journal of Medicine 2019;380:289-91.
From the Sir William Dunn School of Pathology (M.H.B.) and the Kennedy Institute of Rheumatology (M.L.D.), University of Oxford, Oxford, United Kingdom.
Chimeric antigen receptor (CAR) T cells have been strikingly successful in the treatment of hematologic cancers but have not been effective against solid tumors thus far. A recent report by Samaha and colleagues presents a preclinical version of CAR T-cell therapy for a solid tumor, glioblastoma. These investigators engineered a CAR T cell to express a homing molecule (an adhesion molecule), which allows it to tether to and then migrate through the endothelial cells that make up the vasculature perfusing a mouse model of glioblastoma. Their approach is built on the detailed study of tumor endothelial phenotypes and adhesion pathways that affect T-cell endothelial transmigration.
嵌合抗原受体(CAR) T细胞在白血病的治疗中获得了明显成功，但迄今为止尚未证实其对实体肿瘤有效的治疗作用。Samaha及其同事最近报告了CAR T细胞治疗一种实体肿瘤—胶质母细胞瘤的临床前试验。这些研究人员设计了一种CAR T细胞来表达一种归巢分子(一种粘附分子)，这种分子允许CAR T细胞粘附并穿过组成脉管系统的内皮细胞，让CAR T细胞漫布胶质母细胞瘤小鼠模型。他们的方法建立在对肿瘤内皮细胞的表型和影响T细胞内皮转运的粘附通路仔细研究的基础上。
Complications of natalizumab, a drug targeting an integrin adhesion molecule used in the treatment of multiple sclerosis, have taught us that immune cells normally cross the blood–brain barrier and carry out surveillance of the central nervous system (CNS) for viral infection. Samaha et al. started with the observation that the endothelium of the vasculature that supplies glioblastomas down-regulates ligands of the integrin adhesins, which are expressed by effector T cells and are pivotal to most mechanisms governing access to the CNS, but up-regulates an alternative homing ligand, the activated leukocyte cell adhesion molecule (ALCAM), otherwise known as CD166.
纳塔利珠单抗(natalizumab)是一种靶向整合素粘附分子的药物，用于治疗多发性硬化症。它的并发症告诉我们，免疫细胞通常会穿过血脑屏障，监视中枢神经系统(central neurosystem, CNS)的病毒感染。Samaha等人最开始观察到供应胶质母细胞瘤的血管内皮细胞下调整合素粘附素配体, 而这些黏附素配体是效应T细胞表达的，对控制中枢神经系统通路的大多数机制都至关重要。同时，这些内皮细胞又上调了另一种归巢配体，即活化的白细胞黏附分子(ALCAM)，CD166。
ALCAM binds to a transmembrane receptor on T cells, CD6, which facilitates T-cell migration across the blood–brain barrier into the CNS. Samaha et al. found that the forced expression of an engineered CD6-based homing system by CAR T cells effectively steered these engineered cells into the tumor and improved control of glioblastoma in an orthotopic model. The study supports a new phase of engineering of CAR T cells and provides lessons that may be useful in the design of future immunotherapies.、
ALCAM与T细胞上的跨膜受体CD6结合，促进T细胞穿过血脑屏障进入中枢神经系统。Samaha等人发现，CAR T细胞强表达的一种基于CD6的人工设计的归巢系统，可以有效地将这些“工程细胞”引导到肿瘤中，并在原位模型中增强了对胶质母细胞瘤的控制。这项研究推动CAR T细胞工程进入一个新阶段，并提供了可能对未来免疫疗法的设计有借鉴意义。
First, Samaha et al. modified CD6 to work as a homing system. The CD6 protein normally contains three domains, called scavenger receptor cysteine-rich (SRCR) domains, but only one of these domains, the one that is proximal to the transmembrane region, binds ALCAM. The authors reasoned that if they could engineer a CD6 molecule that presented multiple binding domains to ALCAM, they could increase the adhesion of the T cell to the vascular endothelium and thus initiate the next wave of adhesion necessary for transmigration.
The rationale for removal of the two N-terminal SRCR domains was based not only on their lack of direct interaction with ALCAM but also on the observation that their presence in native CD6 might hinder ligand recognition. They created three different new versions of CD6, with one, three, and five copies of the membrane proximal SRCR domain of native CD6 (see Fig. 1 for a depiction of one of these) and tested these in orthotopic mouse models of glioblastoma and medulloblastoma.
They observed that T cells that expressed the homing system have improved homing to these tumors when injected intravenously. The process was selective for tumor endothelium, with no detection of infiltration into normal brain tissue, and preferential recruitment of engineered as compared with normal T cells was not observed in kidney, spleen, and lungs in these mice.
Second, the authors took advantage of a remarkable natural feature of the cytoplasmic region of the CD6 molecule to enhance transendothelial migration, through its “inside-out” activation of T-cell integrins, including lymphocyte function– associated antigen 1 (LFA-1). The ligands of LFA-1, expressed on the vascular endothelial cells of glioblastomas, are suppressed but still present. One of these ligands is intercellular adhesion molecule 1 (ICAM-1).
第二，作者利用CD6分子胞浆区域的一个显著的自然特征，通过T细胞整合素(包括淋巴细胞功能相关抗原1 (LFA-1))的“由内向外”激活，增强了跨上皮细胞迁移。胶质母细胞瘤血管内皮细胞上表达的LFA-1配体被抑制，但仍存在。其中一种配体是细胞间粘附分子1 (ICAM-1)。
The engagement of the engineered CD6 homing receptors by up-regulated ALCAM resulted sequentially in the activation of LFA-1, its highaffinity binding to ICAM-1, changes in the shape of the CAR T cell to increase contact with the endothelium, and then transmigration through the endothelium and into the tumor. Interaction with the endothelium did not require engagement by the CAR. The authors verified the effect of this homing system in promoting CAR T-cell interaction with tumor vasculature, entry into the tumor, and improved tumor control and longer survival in the mouse model of glioblastoma (Fig. 2).
通过上调ALCAM与工程CD6归巢受体的结合，LFA-1继而活化，其高粘附性与ICAM-1结合，CAR - T细胞的形态发生改变，增加与内皮的接触，进而通过内皮转运进入肿瘤。与内皮细胞的相互作用不需要嵌合体抗原的参与。作者验证了该归巢系统在促进CAR - T细胞与肿瘤血管系统相互作用、进入肿瘤、改善肿瘤控制、延长胶质母细胞瘤小鼠模型生存等方面的作用。
Thus, the CD6 cytoplasmic domain will probably be a useful module in engineering other homing systems with different targets. CD6 has the longest cytoplasmic region of the noncatalytic tyrosine phosphorylated immunoreceptors. Complementary to engineering of the extracellular region, development of homing systems may involve isolation of sequences in the CD6 cytoplasmic tail that are crucial for its activating effects.
The design of this homing system was based on fundamental observations made in the context of understanding how cell-surface receptors regulate the immune system at a molecular level. There are many potential barriers to the function of CAR T cells in solid tumors, but similar rational approaches may lead in the future to a tool kit to engineer designer CAR T cells from safety-tested modules that can be implemented in combination to target molecular phenotypes of different solid tumors.