工程CD47保护T细胞增强抗肿瘤免疫-动脉网

Engineered CD47 protects T cells for enhanced antitumour immunity

Nature 等信源发布 2024-05-15 22:55

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AbstractAdoptively transferred T cells and agents designed to block the CD47–SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors.

摘要过继转移的T细胞和旨在阻断CD47-SIRPα轴的药物是有前途的癌症治疗剂，可激活免疫系统的不同臂1,2。在这里，我们将抗CD47抗体与过继转移的T细胞联合施用，目的是增强抗肿瘤功效，但由于巨噬细胞介导的表达嵌合抗原受体（CAR）或工程化T细胞受体的T细胞的快速清除，观察到治疗益处被消除。

Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a ‘don’t eat me’ signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment.

抗CD47抗体介导的CAR T细胞清除是有效且快速的，足以作为有效的安全开关。为了克服这一挑战，我们设计了CD47变体CD47（Q31P）（47E），它与SIRPα结合并提供不被抗CD47抗体阻断的“不吃我”信号。表达47E的TCR或CAR T细胞在用抗CD47抗体处理后对巨噬细胞的清除具有抗性，并介导大量持续的巨噬细胞募集到肿瘤微环境中。

Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages.

尽管许多募集的巨噬细胞表现出M2样特征3，但联合治疗协同增强了抗肿瘤功效。我们的研究将巨噬细胞确定为T细胞持久性的主要调节剂，并说明了将T细胞定向疗法与旨在激活巨噬细胞的疗法相结合的基本挑战。

It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours..

它提供了一种治疗方法，能够同时利用T细胞和巨噬细胞的抗肿瘤作用，提供增强的抗实体瘤效力。。

MainMyeloid cells are the most plentiful immune cells within the tumour microenvironment (TME) and there has been great interest in therapeutically targeting them for antitumour effects2. Increased levels of tumour-associated macrophages (TAMs) associate with poorer outcomes in numerous studies, and some preclinical data demonstrate that reducing or eliminating TAMs enhances responses to chemotherapy and immunotherapy4,5.

骨髓细胞是肿瘤微环境（TME）中最丰富的免疫细胞，人们对治疗靶向它们的抗肿瘤作用非常感兴趣2。在许多研究中，肿瘤相关巨噬细胞（TAM）水平的升高与较差的结果相关，一些临床前数据表明，减少或消除TAM可增强对化疗和免疫治疗的反应4,5。

However, despite dozens of clinical studies testing agents such as CSF1R and CCR2 inhibitors to deplete TAMs and tumour-associated myeloid cells, a clear clinical benefit has not been demonstrated2,4,5. Alternatively, increased TAM density is correlated with improved clinical outcomes in some cancers2, and augmenting TAM phagocytic activity by blocking the CD47–SIRPα axis mediates antitumour effects in several preclinical models6,7,8,9.

然而，尽管有数十项临床研究测试了CSF1R和CCR2抑制剂等药物以消耗TAM和肿瘤相关的骨髓细胞，但尚未证明明显的临床益处2,4,5。或者，增加TAM密度与某些癌症的临床结果改善相关2，并且通过阻断CD47-SIRPα轴来增强TAM吞噬活性在几种临床前模型中介导抗肿瘤作用6,7,8,9。

Clinical trials of CD47–SIRPα axis blockers demonstrated antitumour activity in some liquid tumours when combined with additional agents, but clinical evidence for single-agent activity or activity in solid cancers is lacking10,11,12. Thus, despite extensive effort, therapeutic approaches to target TAMs for clinical benefit are lacking.Anti-CD47 abrogates CAR T and TCR T cell efficacyTo test the hypothesis that augmenting macrophage phagocytosis through CD47 blockade could improve efficacy of CAR T cell therapy, we administered HER2-BBζ CAR T cells with or without the anti-CD47 monoclonal antibody B6H12 to mice bearing 143B osteosarcoma xenografts.

CD47-SIRPα轴阻滞剂的临床试验表明，当与其他药物联合使用时，某些液体肿瘤具有抗肿瘤活性，但缺乏单一药物活性或实体癌活性的临床证据10,11,12。因此，尽管付出了巨大的努力，但缺乏针对TAM的临床益处的治疗方法。抗CD47消除CAR T和TCR T细胞功效为了验证通过CD47阻断增强巨噬细胞吞噬作用可以提高CAR T细胞治疗功效的假设，我们向携带143B骨肉瘤异种移植物的小鼠施用了有或没有抗CD47单克隆抗体B6H12的HER2-BBζCAR T细胞。

CAR T cells alone induced antitumour effects, but the addition of anti-CD47 antibodies ablated CAR T cell efficacy (Fig. 1a and Extended Data Fig. 1a). Similar antagonism was observed with MG63.3 osteosarcoma and D425 medulloblastoma (Fig. 1b and Extended Data Fig. 1b–d). To .

CAR T细胞单独诱导抗肿瘤作用，但抗CD47抗体的加入消除了CAR T细胞的功效（图1a和扩展数据图1a）。MG63.3骨肉瘤和D425髓母细胞瘤也观察到类似的拮抗作用（图1b和扩展数据图1b–d）。到。

Ribonucleoprotein (RNP) was prepared using synthetic sgRNA with 2′-O-methyl phosphorothioate modification (Synthego) diluted in TE buffer at 120 μM. A total of 5 μl sgRNA was incubated with 2.5 μl duplex buffer (IDT) and 2.5 μg Alt-R Streptococcus pyogenes Cas9 Nuclease V3 (IDT) for 30 min at room temperature.

用2′-O-甲基硫代磷酸酯修饰的合成sgRNA（Synthego）在TE缓冲液中稀释120倍，制备核糖核蛋白（RNP）微米。总共5个 μl sgRNA与2.5孵育 μl双链缓冲液（IDT）和2.5 g Alt-R化脓性链球菌Cas9核酸酶V3（IDT）30 在室温下最小。

Reactions (100 μl) were assembled with 5 million T cells or Jurkat cells, 90 μl P3 buffer (Lonza) and 10 μl RNP. Cells were pulsed with protocol EO115 using the P3 Primary Cell 4D-Nucleofector Kit and 4D-Nucleofector System (Lonza). Cells were recovered immediately with warm medium for 6 h before transduction with CAR or TCR.

反应（100 l）与5 百万T细胞或Jurkat细胞，90 l P3缓冲液（Lonza）和10 使用P3原代细胞4D Nucleofector试剂盒和4D Nucleofector系统（Lonza），用EO115方案脉冲μlRNP细胞。立即用温热培养基回收细胞6 h在用CAR或TCR转导之前。

Cells were electroporated with RNP on day 2 after thaw and transduced later the same day. Guide sequences were as follows: CD47, 5′-AUGCUUUGUUACUAAUAUGG-3′; AAVS1, 5′-GGGGCCACUAGGGACAGGAU-3′.Flow cytometry analysis of mammalian cellsCells were washed with FACS buffer (2% FBS in PBS) before staining.

解冻后第2天用RNP电穿孔细胞，并在当天晚些时候转导。指导序列如下：CD47，5'-Augcuuuuuacuaauaugg-3'；AAVS1，5'-GGGGCCACUAGGGACAGGAU-3'。哺乳动物细胞的流式细胞术分析在染色前用FACS缓冲液（PBS中的2%FBS）洗涤细胞。

Staining was performed in FACS buffer for 30 min at 4 °C. In certain experiments, cells were first stained with Fixable Viability Dye eFluor 780 (eBioscience, 1:2,000) in PBS for 10 min at room temperature before washing with FACS buffer and staining with other antibodies. After staining, cells were then washed once with FACS buffer and analysed on the BD Fortessa system.

在FACS缓冲液中染色30 最小值为4 °C。在某些实验中，首先将细胞用PBS中的可固定活力染料eFluor 780（eBioscience，1:2000）染色10 在室温下放置分钟，然后用FACS缓冲液洗涤并用其他抗体染色。染色后，然后用FACS缓冲液洗涤细胞一次，并在BD Fortessa系统上进行分析。

FACSDiva (v.8.0.1; BD) software was used for data collection and FlowJo software (v.10.8.1; BD) was used for data analysis (gating strategies are shown in Supplementary Fig. 2).Recombinant B7H3-Fc and HER2-Fc (both R&D systems, 1:400 dilution) were used to detect B7H3 and HER2 surface CAR, respectively.

FACSDiva（v.8.0.1；BD）软件用于数据收集，FlowJo软件（v.10.8.1；BD）用于数据分析（门控策略如补充图2所示）。重组B7H3-Fc和HER2-Fc（均为R＆D systems，1:400稀释度）分别用于检测B7H3和HER2表面CAR。

Likewise, anti-FMC63 idiotype antibody (Genscript, 1:400) was used to detect CD19 CARs, while anti-14G2a idiotype antibody (National Cancer Institute, 1:400) was used to detect GD.

同样，使用抗FMC63独特型抗体（Genscript，1:400）检测CD19 CAR，而使用抗14G2a独特型抗体（National Cancer Institute，1:400）检测GD。

Data availability

数据可用性

All data associated with this paper are included in the Article and the Supplementary Information. The scRNA-seq dataset has been deposited at the NCBI Gene Expression Omnibus (GEO) under accession number GSE261475. Data used to generate scRNA-seq UMAP plots from patient data (Fig. 2d) were obtained from publicly available datasets using the GEO series accession numbers GSE168940 (ref.

与本文相关的所有数据均包含在文章和补充信息中。scRNA-seq数据集已以登录号GSE261475保藏在NCBI Gene Expression Omnibus（GEO）上。用于从患者数据生成scRNA-seq UMAP图的数据（图2d）是使用GEO系列登录号GSE168940（参考文献）从公开可用的数据集中获得的。

14) and GSE186802 (ref. 15). For protein crystal structure modelling, the following publicly availably PDB files were used: 2JJS (hCD47–hSIRPa) and 5TZU (hCD47–B6H12). Source data are provided with this paper..

14）和GSE186802（参考文献15）。对于蛋白质晶体结构建模，使用了以下公开可用的PDB文件：2JJS（hCD47–hSIRPa）和5ZI（hCD47–B6H12）。本文提供了源数据。。

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Download referencesAcknowledgementsThis work was supported by National Institutes of Health grants 1R01CA263500-01 (C.L.M. and M.M.); an EPICC Translational Research Grant (St Baldrick’s Foundation, C.L.M.); and the Virginia and D.K. Ludwig Fund for Cancer Research (C.L.M.). C.L.M., S.A.Y.-H., L.L.

下载参考文献致谢这项工作得到了美国国立卫生研究院拨款1R01CA263500-01（C.L.M.和M.M.）的支持；EPICC转化研究基金（St Baldrick's Foundation，C.L.M.）；以及弗吉尼亚州和D.K.路德维希癌症研究基金（C.L.M.）。C、 L.M.，S.A.Y.-H.，L.L。

and Z.G. are members of the Parker Institute for Cancer Immunotherapy, which supports the Stanford University Cancer Immunotherapy Program. B.J.M. was supported by a Stanford Interdisciplinary Graduate Fellowship; K.A.F. by the National Science Foundation Graduate Research Fellowship under grant DGE-1656518; F.L.

和Z.G.是帕克癌症免疫治疗研究所的成员，该研究所支持斯坦福大学癌症免疫治疗计划。B、 J.M.得到了斯坦福跨学科研究生奖学金的支持；K、由国家科学基金会研究生研究奖学金授予DGE-1656518；F、 L。

by a Stanford M-TRAM Capstone project grant; A.L. by the Nuovo-Soldati Foundation and by ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Santé/National Alliance for the Life Sciences and Health) within the framework of the French Cancer Plan; R.P. by the Princess Máxima Center for Pediatric Oncology and Academy Ter Meulen Fund of the Royal Netherlands Academy of Arts & Sciences; S.H.

斯坦福M-TRAM Capstone项目赠款；A、 L.由Nuovo Soldati基金会和ITMO Cancer AVIESAN（国家生命科学与健康联盟/国家生命科学与健康联盟）在法国癌症计划的框架内；R、 P.由荷兰皇家艺术与科学学院Máxima公主儿科肿瘤学中心和Ter Meulen学院基金；S、 H。

by a U54 CA232568-01 grant; and O.K. by a Paul and Daisy Soros Fellowship for New Americans. J.B. received support from the Stanford Biosciences Training grant 5T32-GM11999505 through the Institute for Stem Cell Biology & Regenerative Medicine, and the National Science Foundation Graduate Research Fellowship Program under Award Number 2146755; T.M.

通过U54 CA232568-01拨款；保罗·索罗斯和黛西·索罗斯为新美国人设立的奖学金。J、 B.通过干细胞生物学与再生医学研究所获得斯坦福生物科学培训基金5T32-GM11999505的支持，以及国家科学基金会研究生研究奖学金项目，奖项编号2146755；T、 M。

from the Stanford Medical Scientist Training Program grant T32GM007365, the NCI under Award Number F30CA271797, the Stanford Interdisciplinary Graduate Fellowship, the Stanford ChEM-H Chemistry/Biology Interface Predoctoral Training Program and the Stanford ChEM-H O’Leary-Thiry Graduate Fellowship. Sorting was performed on an instrument at the Stanford Shared FACS Facility obtained using NIH S10 Sha.

来自斯坦福医学科学家培训计划拨款T32GM007365，NCI奖项编号F30CA271797，斯坦福跨学科研究生奖学金，斯坦福化学/生物学界面博士前培训计划和斯坦福化学-化学-化学-奥利里-第三研究生奖学金。在使用NIH S10 Sha获得的斯坦福共享FACS设施的仪器上进行分选。

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PubMed Google ScholarContributionsS.A.Y.-H., J.T. and C.L.M. conceived the idea of the study. S.A.Y.-H. designed experiments, cloned constructs, performed in vitro characterizations, including phagocytosis assays, in vivo experiments, protein engineering and yeast binding characterization experiments, and scRNA-seq experiments, including analysing and interpreting data.

PubMed谷歌学术贡献。A、 Y.-H.，J.T.和C.L.M.构思了这项研究的想法。S、 A.Y.-H.设计实验，克隆构建体，进行体外表征，包括吞噬作用测定，体内实验，蛋白质工程和酵母结合表征实验，以及scRNA-seq实验，包括分析和解释数据。

J.T. designed experiments, cloned constructs and performed in vitro characterizations, including phagocytosis assays, and in vivo experiments, including analysing and interpreting data. B.J.M. conducted protein engineering and yeast binding characterization experiments, analysed data and interpreted results.

J、 T.设计实验，克隆构建体并进行体外表征，包括吞噬作用测定，以及体内实验，包括分析和解释数据。B、 J.M.进行了蛋白质工程和酵母结合表征实验，分析了数据并解释了结果。

K.A.F. performed experiments, analysed data and interpreted results relating to scRNA-seq. F.L., M.T.R. and S.D. cloned constructs, performed in vitro characterizations and conducted in vivo studies. A.L. designed and characterized the PIP CAR toxicity model, including performing experiments, analysing data and interpreting results.

K、 A.F.进行了实验，分析了数据并解释了与scRNA-seq相关的结果。F、 L.，M.T.R.和S.D.克隆的构建体，进行了体外表征并进行了体内研究。A、 L.设计并表征了PIP CAR毒性模型，包括进行实验，分析数据和解释结果。

N.M.-V. designed in vivo experiments, assisted with tumour dissociation studies, and designed, analysed and interpreted flow cytometry experiments. P.X. and J.H. organized and conducted in vivo studies. A.D. performed IHC experiments and analysed and interpreted data. M.H.D. performed scRNA-seq experiments.

N、 M.-V.设计了体内实验，协助肿瘤解离研究，并设计，分析和解释了流式细胞术实验。P、 X.和J.H.组织并进行了体内研究。A、 D.进行IHC实验并分析和解释数据。M、 H.D.进行了scRNA-seq实验。

Z.G. and Y.C. analysed scRNA-seq data and interpreted results. R.P. designed and performed confocal experiments, including analysing data and interpreting results. A.M. performed phagocytosis assays. L.L. cloned constructs and designed experiments. J.B. performed in vitro characterizations and flow cytometry experiments.

Z、 G.和Y.C.分析了scRNA-seq数据并解释了结果。R、 P.设计并进行共焦实验，包括分析数据和解释结果。A、 M.进行吞噬作用测定。五十、 L.克隆构建体和设计实验。J、 B.进行体外表征和流式细胞术实验。

T.M. and Z.E. analysed flow cytometry data and interpreted results. C.W.M. performed in vivo studies and histology analysis an.

T、 M.和Z.E.分析了流式细胞术数据并解释了结果。C、 W.M.进行了体内研究和组织学分析。

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Competing interests

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S.A.Y.-H., J.T., B.J.M., J.R.C. and C.L.M. are listed as coinventors on a patent related to this work (PCT/US2024/013209, submitted by the board of trustees of the Leland Stanford Junior University). C.L.M. holds equity in CARGO Therapeutics, Link Cell Therapies and Ensoma, which are developing CAR-based therapies; consults for CARGO, Link, Immatics, Ensoma and Red Tree Capital; and receives research funding from Lyell Immunopharma and Tune Therapeutics.

S、 A.Y.-H.，J.T.，B.J.M.，J.R.C.和C.L.M.被列为与这项工作相关的专利的共同发明人（PCT/US2024/013209，由利兰斯坦福初级大学董事会提交）。C、 L.M.持有CARGO Therapeutics、Link Cell Therapeutics和Ensoma的股权，这些公司正在开发基于CAR的疗法；咨询CARGO、Link、Immatics、Ensoma和Red Tree Capital；并获得Lyell Immunopharma和Tune Therapeutics的研究资助。

S.A.Y.-H. is a consultant for Quince Therapeutics. J.T. is a consultant for Dorian Therapeutics. L.L. and E.S. are consultants for and hold equity in Lyell Immunopharma. L.L. is a cofounder of, consults for and holds equity in CARGO Therapeutics. O.K. is a senior fellow with ARTIS Ventures. C.J.K. is founder and scientific advisory board member for NextVivo, Surrozen and Mozart Therapeutics.

S、 A.Y.-H.是Quince Therapeutics的顾问。J、 T.是Dorian Therapeutics的顾问。五十、 L.和E.S.是Lyell Immunopharma的顾问并持有其股权。五十、 L.是CARGO Therapeutics的联合创始人、顾问和股东。O、 K.是ARTIS Ventures的高级研究员。C、 J.K.是NextVivo、Surrozen和Mozart Therapeutics的创始人和科学顾问委员会成员。

R.G.M. is a co-founder of and holds equity in Link Cell Therapies; and is a consultant for NKarta, Arovella Pharmaceuticals, Innervate Radiopharmaceuticals, GammaDelta Therapeutics, Aptorum Group, Zai Labs, Immunai, Gadeta, FATE Therapeutics (DSMB) and Waypoint Bio. I.L.W. is a director, stockholder in and consultant for Forty Seven (but not Gilead); a co-founder of and director and consultant for Bitterroot Bio and PHeast, and a co-founder of 48.

R、 G.M.是Link Cell Therapes的联合创始人并持有其股权；并且是NKarta、Arovella Pharmaceuticals、Nervate Radiopharmaticals、GammaDelta Therapeutics、Aptorum Group、Zai Labs、Immunai、Gadeta、FATE Therapeutics（DSMB）和Waypoint Bio的顾问。I.L.W.是47位董事、股东和顾问（但不是Gilead）；Bitterroot Bio和PHeast的联合创始人、董事和顾问，48岁的联合创始人。

I.L.W. is also on the scientific advisory board of Appia. E.S consults for Lepton Pharmaceuticals and Galaria. J.R.C. is a cofounder and equity holder of Trapeze Therapeutics, Combangio and Virsti Therapeutics; has financial interests in Aravive, Xyence Therapeutics and CARGO Therapeutics; and is a member of the board of directors of Ligand Pharmaceuticals and Revel Pharmaceuticals.

一、 L.W.也是Appia科学顾问委员会的成员。E、 S为Lepton Pharmaceuticals和Galaria提供咨询。J.R.C.是Trapeze Therapeutics，Combangio和Virsti Therapeutics的联合创始人和股东；在Aravive、Xyence Therapeutics和CARGO Therapeutics拥有财务利益；并且是Ligand Pharmaceuticals和Revel Pharmaceuticals董事会成员。

The other authors declare no competing interests..

其他作者声明没有利益冲突。。

Peer review

同行评审

Peer review information

同行评审信息

Nature thanks Smita Chandran and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

《自然》杂志感谢Smita Chandran和另一位匿名审稿人为这项工作的同行评审做出的贡献。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended data figures and tablesExtended Data Fig. 1 Anti-CD47 therapy blunts CAR and TCR T cell efficacy by depleting adoptively transferred T cells.(a) Her2.BBζ-CAR ± B6H12 treated 143B tumour survival.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。扩展数据图和表扩展数据图1抗CD47治疗通过消耗过继转移的T细胞来钝化CAR和TCR T细胞功效。（a） Her2.BBζ-汽车 ± B6H12治疗143B肿瘤存活。

n = 5 mice/arm. (b) B7H3.BBζ- or GD2.BBζ-CAR ± B6H12 treated MG63.3 tumour survival. n = 5 mice/arm. (c) B7H3.BBζ-CAR ± B6H12 treated D425 tumour growth by BLI. CD19.BBζ-CAR is included as a non-tumour targeting control. Mean ± SEM of n = 5 (B6H12) or n = 6 (all others) mice/arm. Representative of two independent experiments.

n = 5只小鼠/手臂。（b） B7H3.BBζ-或GD2.BBζ-CAR ± B6H12治疗MG63.3肿瘤存活率。n = 5只小鼠/手臂。（c） B7H3.BBζ-汽车 ± B6H12通过BLI处理D425肿瘤生长。CD19。BBζ-CAR被包括作为非肿瘤靶向对照。平均值 ± n的SEM = 5（B6H12）或n = 6只（所有其他）小鼠/手臂。代表两个独立的实验。

(d) B7H3.BBζ-CAR ± B6H12 treated D425 tumour survival. CD19.BBζ-CAR is included as a non-tumour targeting control. n = 5 (B6H12) or n = 6 (all others) mice per treatment arm. Representative of two independent experiments. (e) Representative flow cytometry plots of hCD45+ T cells identified in the blood and tumour in the B7H3.BBζ-CAR ± B6H12 treated MG63.3 model on day 30 post tumour engraftment.

（d） B7H3.BBζ-汽车 ± B6H12治疗的D425肿瘤存活率。包括CD19.BBζ-CAR作为非肿瘤靶向对照。n = 5（B6H12）或n = 每个治疗组6只（所有其他）小鼠。代表两个独立的实验。（e）在B7H3.BBζ-CAR的血液和肿瘤中鉴定的hCD45+T细胞的代表性流式细胞术图 ± B6H12在肿瘤植入后第30天处理MG63.3模型。

(f) Representative flow cytometry plots of hCD45+ T cells identified in the blood of non-tumour bearing mice co-treated with CD19.28ζ-CAR T cells and either PBS, B6H12, or mIgG1 isotype control. Representative of two independent experiments. (g) hCD8+ (top) and hCD4+ (bottom) T cells in the blood of mice on day 5 in the isotype control model, treated as in (f).

（f）在用CD19.28ζ-CAR T细胞和PBS，B6H12或mIgG1同种型对照共同处理的非荷瘤小鼠的血液中鉴定的hCD45+T细胞的代表性流式细胞术图。代表两个独立的实验。（g）在同种型对照模型的第5天，小鼠血液中的hCD8+（顶部）和hCD4+（底部）T细胞，如（f）中处理。

Mean ± SD of n = 5 mice. Representative of two independent experiments. (h) T cells (hCD4+ and hCD8+) in the blood of mice on day 12 in Her2.BBζ ± B6H12 treated mice in the 143B model. Mean ± SD of n = 5 mice. (i) Low-dose NY-ESO-1-TCR ± B6H12 treated A375 tumour survival. n = 5 mice/arm. (j) High-dose NY-ESO-1-TCR ± B6H12 treated A375 tumour gr.

平均值 ± n的SD = 5只小鼠。代表两个独立的实验。（h） Her2第12天小鼠血液中的T细胞（hCD4+和hCD8+）。143B模型中BBζ±B6H12处理的小鼠。平均值 ± n的SD = 5只小鼠。（i）低剂量NY-ESO-1-TCR ± B6H12治疗A375肿瘤存活。n = 5只小鼠/手臂。（j）大剂量NY-ESO-1-TCR ± B6H12治疗的A375肿瘤gr。

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

开放获取本文是根据知识共享署名4.0国际许可证授权的，该许可证允许以任何媒体或格式使用，共享，改编，分发和复制，只要您对原始作者和来源给予适当的信任，提供知识共享许可证的链接，并指出是否进行了更改。

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/..

要查看此许可证的副本，请访问http://creativecommons.org/licenses/by/4.0/..

Reprints and permissionsAbout this articleCite this articleYamada-Hunter, S.A., Theruvath, J., McIntosh, B.J. et al. Engineered CD47 protects T cells for enhanced antitumour immunity.

转载和许可本文引用本文Yamada Hunter，S.A.，Theruvath，J.，McIntosh，B.J。等人。工程CD47保护T细胞以增强抗肿瘤免疫力。

Nature (2024). https://doi.org/10.1038/s41586-024-07443-8Download citationReceived: 08 May 2023Accepted: 18 April 2024Published: 15 May 2024DOI: https://doi.org/10.1038/s41586-024-07443-8Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《自然》（2024）。https://doi.org/10.1038/s41586-024-07443-8Download引文接收日期：2023年5月8日接收日期：2024年4月18日发布日期：2024年5月15日OI：https://doi.org/10.1038/s41586-024-07443-8Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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