小柯机器人

美国加州大学旧金山分校Alexander Marson等研究人员合作发现，T细胞中的RASA2敲除可提高抗原敏感性和长期功能。这一研究成果于2022年8月24日在线发表在《自然》杂志上。

研究人员在不同的免疫抑制条件下进行了多个全基因组CRISPR基因敲除筛选，从而确定可用于防止T细胞功能障碍的基因。这些筛选的结果是RASA2，一种RAS GTP酶激活蛋白（RasGAP），研究人员将其确定为人类T细胞的信号检查点，在急性T细胞受体刺激时下调，并可随着慢性抗原暴露逐渐增加。RASA2敲除增强了MAPK信号和嵌合抗原受体（CAR）T细胞对靶标抗原的细胞溶解活性。体外重复的肿瘤抗原刺激显示，与对照组细胞相比，RASA2缺陷的T细胞显示出更多的激活、细胞因子的产生和代谢活性，并在持续的癌细胞杀伤方面表现出明显的优势。在白血病的小鼠模型中，RASA2基因敲除的CAR T细胞在骨髓中比对照细胞具有竞争性的适应性优势。在T细胞受体和CAR T细胞疗法的多个临床前模型中，RASA2的敲除延长了血液或实体肿瘤异种移植小鼠的生存期。

总之，这些研究结果强调RASA2是一个很有前途的靶标，可以提高T细胞疗法治疗癌症的持久性和效应功能。

据介绍，过继性T细胞疗法治疗癌症的疗效可能受到来自外在因素和内在抑制检查点的抑制信号的限制。靶向基因编辑有可能克服这些限制，增强T细胞的治疗功能。

附：英文原文

Title: RASA2 ablation in T cells boosts antigen sensitivity and long-term function

Author: Carnevale, Julia, Shifrut, Eric, Kale, Nupura, Nyberg, William A., Blaeschke, Franziska, Chen, Yan Yi, Li, Zhongmei, Bapat, Sagar P., Diolaiti, Morgan E., OLeary, Patrick, Vedova, Shane, Belk, Julia, Daniel, Bence, Roth, Theodore L., Bachl, Stefanie, Anido, Alejandro Allo, Prinzing, Brooke, Ibaez-Vega, Jorge, Lange, Shannon, Haydar, Dalia, Luetke-Eversloh, Marie, Born-Bony, Maelys, Hegde, Bindu, Kogan, Scott, Feuchtinger, Tobias, Okada, Hideho, Satpathy, Ansuman T., Shannon, Kevin, Gottschalk, Stephen, Eyquem, Justin, Krenciute, Giedre, Ashworth, Alan, Marson, Alexander

Issue&Volume: 2022-08-24

Abstract: The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints1,2. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function3,4,5,6,7,8,9,10. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. These screens converged on RASA2, a RAS GTPase-activating protein (RasGAP) that we identify as a signalling checkpoint in human T cells, which is downregulated upon acute T cell receptor stimulation and can increase gradually with chronic antigen exposure. RASA2 ablation enhanced MAPK signalling and chimeric antigen receptor (CAR) T cell cytolytic activity in response to target antigen. Repeated tumour antigen stimulations in vitro revealed that RASA2-deficient T cells show increased activation, cytokine production and metabolic activity compared with control cells, and show a marked advantage in persistent cancer cell killing. RASA2-knockout CAR T cells had a competitive fitness advantage over control cells in the bone marrow in a mouse model of leukaemia. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumours. Together, our findings highlight RASA2 as a promising target to enhance both persistence and effector function in T cell therapies for cancer treatment.

DOI: 10.1038/s41586-022-05126-w

Source: https://www.nature.com/articles/s41586-022-05126-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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