從SCI論文里學英語

從論文中學習英語，用到自己的文章中，今天帶來的文章題目為《將CAR - T細胞引入實體瘤》。

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.

嵌合抗原受體(CAR) T細胞在白血病的治療中獲得了明顯成功，但迄今為止尚未證實其對實體腫瘤有效的治療作用。Samaha及其同事最近報告了CAR T細胞治療一種實體腫瘤—膠質母細胞瘤的臨床前試驗。這些研究人員設計了一種CAR T細胞來表達一種歸巢分子(一種粘附分子)，這種分子允許CAR T細胞粘附并穿過組成脈管系統(tǒng)的內皮細胞，讓CAR T細胞漫布膠質母細胞瘤小鼠模型。他們的方法建立在對腫瘤內皮細胞的表型和影響T細胞內皮轉運的粘附通路仔細研究的基礎上。

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.

納塔利珠單抗(natalizumab)是一種靶向整合素粘附分子的藥物，用于治療多發(fā)性硬化癥。它的并發(fā)癥告訴我們，免疫細胞通常會穿過血腦屏障，監(jiān)視中樞神經系統(tǒng)(central neurosystem, CNS)的病毒感染。Samaha等人最開始觀察到供應膠質母細胞瘤的血管內皮細胞下調整合素粘附素配體, 而這些黏附素配體是效應T細胞表達的，對控制中樞神經系統(tǒng)通路的大多數(shù)機制都至關重要。同時，這些內皮細胞又上調了另一種歸巢配體，即活化的白細胞黏附分子(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與T細胞上的跨膜受體CD6結合，促進T細胞穿過血腦屏障進入中樞神經系統(tǒng)。Samaha等人發(fā)現(xiàn)，CAR T細胞強表達的一種基于CD6的人工設計的歸巢系統(tǒng)，可以有效地將這些“工程細胞”引導到腫瘤中，并在原位模型中增強了對膠質母細胞瘤的控制。這項研究推動CAR T細胞工程進入一個新階段，并提供了可能對未來免疫療法的設計有借鑒意義。

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.

首先，Samaha等人對CD6進行了改良，使其成為一個歸巢系統(tǒng)。CD6蛋白通常包含三個結構域，稱為清道夫受體半胱氨酸富集(SRCR)結構域，但只有其中一個結構域(接近跨膜區(qū)域的結構域)可與ALCAM結合。作者推斷，如果他們能夠設計出一種CD6分子，使其與ALCAM表達多個結合域，那么他們就可以增加T細胞與血管內皮的粘附，從而啟動遷移所需的下級粘附。

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.

去除這兩個N端SRCR區(qū)域的原因不僅在于它們與ALCAM缺乏直接的相互作用，還在于觀察到它們在天然CD6中的存在可能阻礙配體識別。他們創(chuàng)造了三種不同的新CD6版本，包括一個、三個和五個天然CD6的膜近端SRCR區(qū)域拷貝并在成膠質細胞瘤和成神經管細胞瘤的原位小鼠模型中進行了實驗。

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.

他們觀察到，表達該歸巢系統(tǒng)的T細胞在靜脈注射時改善了在這些腫瘤中的歸巢。該過程對腫瘤內皮細胞具有選擇性，未檢測到正常腦組織的浸潤，且與正常T細胞相比，未在小鼠腎臟、脾臟和肺中觀察到“工程細胞”被優(yōu)先招募的情況。

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分子胞漿區(qū)域的一個顯著的自然特征，通過T細胞整合素(包括淋巴細胞功能相關抗原1 (LFA-1))的“由內向外”激活，增強了跨上皮細胞遷移。膠質母細胞瘤血管內皮細胞上表達的LFA-1配體被抑制，但仍存在。其中一種配體是細胞間粘附分子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).

通過上調ALCAM與工程CD6歸巢受體的結合，LFA-1繼而活化，其高粘附性與ICAM-1結合，CAR - T細胞的形態(tài)發(fā)生改變，增加與內皮的接觸，進而通過內皮轉運進入腫瘤。與內皮細胞的相互作用不需要嵌合體抗原的參與。作者驗證了該歸巢系統(tǒng)在促進CAR - T細胞與腫瘤血管系統(tǒng)相互作用、進入腫瘤、改善腫瘤控制、延長膠質母細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.

因此，CD6細胞質區(qū)域可能是設計其他不同靶向系統(tǒng)的有用模塊。CD6擁有非催化酪氨酸磷酸化免疫感受器中最長的細胞質區(qū)域。作為細胞外區(qū)域工程的補充，歸巢系統(tǒng)的開發(fā)可能涉及分離對其激活作用至關重要的CD6細胞質尾序列。

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.

這個歸巢系統(tǒng)的設計是基于對細胞表面受體如何在分子水平上調節(jié)免疫系統(tǒng)的基本觀察。T細胞對實體腫瘤的作用有許多潛在的障礙,但是類似的合理的方法未來可能會有一種工具箱，從經過安全測試的模塊中設計出CAR T細胞，這些細胞可以結合應用于靶向不同實體腫瘤的分子表型。