AbstractTiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2.

摘要tiragolumab是一种具有活性IgG1κFc的抗TIGIT抗体，当与atezolizumab（抗PD-L1）联合使用时，与单独使用atezolizumab相比，在2期CITYSCAPE试验（ClinicalTrials.gov:NCT03563716）中表现出改善的结果1。然而，关于这种组合的反应机制仍然没有达成共识2。

Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment.

在这里，我们发现肿瘤内巨噬细胞和调节性T细胞的高基线与用atezolizumab加tiragolumab治疗但不单独使用atezolizumab治疗的患者的更好结果相关。血清样本分析显示，巨噬细胞活化与接受联合治疗的患者的临床获益有关。

In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development..

在小鼠肿瘤模型中，tiragolumab替代抗体通过Fcγ受体（FcγR）使肿瘤相关巨噬细胞，单核细胞和树突状细胞发炎，进而将抗肿瘤CD8+T细胞从耗尽的效应物样状态驱动到更像记忆的状态。这些结果揭示了TIGIT检查点抑制剂可以重塑免疫抑制性肿瘤微环境的作用机制，并表明FcγR参与是抗TIGIT抗体开发中的重要考虑因素。。

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Fig. 1: Intratumoural myeloid and Treg cell content is associated with patient benefit after combination treatment with tiragolumab plus atezolizumab in the CITYSCAPE trial.Fig. 2: Treatment with tiragolumab plus atezolizumab leads to increased serum myeloid proteins.Fig. 3: Tiragolumab plus atezolizumab leads to T, NK and myeloid cell activation in PBMCs.Fig.

图1：在CITYSCAPE试验中，用替拉鲁单抗加atezolizumab联合治疗后，肿瘤内骨髓和Treg细胞含量与患者获益相关。图2：用tiragolumab加atezolizumab治疗导致血清髓样蛋白增加。图3:Tiragolumab加atezolizumab导致PBMC中的T，NK和骨髓细胞活化。图。

4: Fc receptor engagement supports tiragolumab surrogate efficacy and ability to remodel the tumour microenvironment in mice.Fig. 5: Flow cytometry analysis of anti-TIGIT antibody activity on tumour myeloid cells and lymphocytes.Fig. 6: Macrophages enable modulation of CD8+ T cells by Fc-active anti-TIGIT antibodies in vivo and in vitro..

4： Fc受体参与支持tiragolumab替代功效和重塑小鼠肿瘤微环境的能力。图5：肿瘤骨髓细胞和淋巴细胞上抗TIGIT抗体活性的流式细胞术分析。图6：巨噬细胞能够在体内和体外通过Fc活性抗TIGIT抗体调节CD8+T细胞。。

Data availability

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The sequencing data generated in this study will be deposited once anonymized. Up-to-date details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents are available online (https://go.roche.com/data_sharing). Anonymized records for individual patients across more than one data source external to Roche cannot, and should not, be linked due to a potential increase in risk of patient re-identification.

这项研究中生成的测序数据将在匿名后保存。有关罗氏全球临床信息共享政策以及如何请求访问相关临床研究文件的最新详细信息，请在线查阅(https://go.roche.com/data_sharing)。由于患者重新识别风险的潜在增加，罗氏外部多个数据源中个别患者的匿名记录不能也不应该链接。

Source data of preclinical study data are provided with this paper, and source data of clinical study data will be deposited once anonymized. Source data are provided with this paper..

本文提供了临床前研究数据的源数据，临床研究数据的源数据将在匿名后保存。本文提供了源数据。。

Code availability

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All packages used in this study are publicly available. This study does not report original codes.

本研究中使用的所有软件包都是公开的。这项研究没有报告原始代码。

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Sergushichev, A. A. An algorithm for fast preranked gene set enrichment analysis using cumulative statistic calculation. Preprint at bioRxiv https://doi.org/10.1101/060012 (2021).Download referencesAcknowledgementsWe thank the patients who provided tumour samples for this study, as well as the investigators and staff involved in the CITYSCAPE study.

Sergushichev，A.A。使用累积统计计算进行快速预排序基因集富集分析的算法。bioRxiv预印本https://doi.org/10.1101/060012（2021年）。下载参考文献致谢我们感谢为本研究提供肿瘤样本的患者，以及参与城市景观研究的研究人员和工作人员。

Editorial assistance for the development of this Article, under the direction of the authors, was provided by A. Robertson and D. Christofi of Ashfield MedComms, an Inizio company, and funded by F. Hoffmann-La Roche. We also thank the staff at Biognosys for processing and generating the raw mass spectrometry data files for analysis; the staff at Abiosciences for generating mouse scRNA-seq raw data files; the staff at Immunai for generating and processing human PBMC scRNA-seq data; and C.

在作者的指导下，本文的编辑协助由Inizio公司Ashfield MedComms的A.Robertson和D.Christofi提供，并由F.Hoffmann La Roche资助。我们也感谢Biognosys的工作人员处理和生成原始质谱数据文件进行分析；Abiosciences的工作人员用于生成鼠标scRNA-seq原始数据文件；Immunai的工作人员负责生成和处理人类PBMC scRNA-seq数据；和C。

Bais, T. Pham, R. Greathouse and A. Rapaport for reading the manuscript and providing technical assistance.Author informationAuthor notesThese authors contributed equally: Xiangnan Guan, Ruozhen Hu, Yoonha Choi, Shyam Srivats, Robert J. Johnston, Namrata S. PatilThese authors jointly supervised this work: Robert J.

Bais，T。Pham，R。Greathouse和A。Rapaport阅读手稿并提供技术援助。作者信息作者注意到这些作者做出了同样的贡献：关湘南，胡若珍，崔永霞，Shyam Srivats，Robert J.Johnston，Namrata S.Patilth这些作者共同监督了这项工作：Robert J。

Johnston, Namrata S. PatilAuthors and AffiliationsGenentech Inc., South San Francisco, CA, USAXiangnan Guan, Ruozhen Hu, Yoonha Choi, Shyam Srivats, Barzin Y. Nabet, John Silva, Lisa McGinnis, Robert Hendricks, Katherine Nutsch, Karl L. Banta, Ellen Duong, Alexis Dunkle, Patrick S. Chang, Chia-Jung Han, Stephanie Mittman, Nandini Molden, Pallavi Daggumati, Wendy Connolly, Ira Mellman, Sanjeev Mariathasan, David S.

Johnston，Namrata S.PatilAuthors及其附属机构Genentech Inc.，南旧金山，加利福尼亚州，USAXiangnan Guan，Ruozhen Hu，Yoonha Choi，Shyam Srivats，Barzin Y.Nabet，John Silva，Lisa McGinnis，Robert Hendricks，Katherine Nutsch，Karl L.Banta，Ellen Duong，Alexis Dunkle，Patrick S.Chang，Chia Jung Han，Stephanie Mittman，Nandini Molden，Pallavi Daggumati，Wendy Connolly，艾拉·梅尔曼（IraMellman），桑杰夫·马里亚萨桑（SanjeevMariathasan），大卫·S。

Shames, Raymond Meng, Eugene Y. Chiang, Robert J. Johnston & Namrata S. PatilSarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USAMelissa JohnsonHospital Universitario Insular de Gr.

Shames，Raymond Meng，Eugene Y.Chiang，Robert J.Johnston＆Namrata S.PatilSarah Cannon Research Institute/田纳西州肿瘤学，PLLC，田纳西州纳什维尔，USAMelissa JohnsonHospital Universitario Isular de Gr。

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PubMed Google ScholarContributionsX.G. and R. Hu are co-first authors; Y.C. and S.S. are co-second authors; and R.J.J. and N.S.P. are co-senior authors. N.S.P. and R.J.J. conceived the project. R. Hu, S.S., J.S., L.M., R. Hendricks, K.N., K.L.B., E.D., P.S.C., J.H. and S. Mittman performed experiments.

PubMed谷歌学术贡献x。G、 和R.Hu是共同的第一作者；Y、 C.和S.S.是共同的第二作者；R.J.J.和N.S.P.是联合高级作者。N。S、 P.和R.J.J.构思了这个项目。R、 胡，S.S.，J.S.，L.M.，R.Hendricks，K.N.，K.L.B.，E.D.，P.S.C.，J.H.和S.Mittman进行了实验。

N.S.P., R.J.J., X.G., R. Hu, Y.C., S.S., B.Y.N., L.M. and E.D analysed data. N.S.P., S.S., E.Y.C., L.M., A.D., S. Mariathasan, R.M., D.S.S., I.M. and R.J.J. guided data analysis. W.C., N.M. and P.D. coordinated clinical sample management and analysis. M.J., D.R.A., B.C.C., A.I., I.G.-B., E.F. and R.M.

N、 S.P.，R.J.J.，X.G.，R.Hu，Y.C.，S.S.，B.Y.N.，L.M.和E.D分析了数据。N、 S.P.，S.S.，E.Y.C.，L.M.，A.D.，S.Mariathasan，R.M.，D.S.S.，I.M.和R.J.J.引导数据分析。W、 C.，N.M.和P.D.协调临床样本管理和分析。M、 J.，D.R.A.，B.C.C.，A.I.，I.G.-B.，E.F.和R.M。

guided clinical trial and data management. N.S.P., R.J.J. and X.G. wrote the manuscript with input from all of the authors. All of the authors contributed to data interpretation, discussion of results and commented on the manuscript.Corresponding authorsCorrespondence to.

指导临床试验和数据管理。N、 S.P.，R.J.J.和X.G.在所有作者的意见下撰写了手稿。所有作者都为数据解释，结果讨论和手稿评论做出了贡献。通讯作者通讯。

Robert J. Johnston or Namrata S. Patil.Ethics declarations

Robert J.Johnston或Namrata S.Patil。道德宣言

Competing interests

相互竞争的利益

X.G., R. Hu, Y.C., S.S., B.Y.N., J.S., L.M., R. Hendricks, K.N., K.L.B., E.D., A.D., P.S.C., J.H., S. Mittman, N.M., P.D., W.C., I.M., S. Mariathasan, D.S.S., R.M., E.Y.C., R.J.J. and N.S.P. are employees and stockholders of Roche/Genentech. M.J. declares research funding (paid to institution) from AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, ArriVent BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Eikon Therapeutics, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Kartos Therapeutics, LockBody Therapeutics, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Taiho Oncology, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, T.

十、 G.，R.Hu，Y.C.，S.S.，B.Y.N.，J.S.，L.M.，R.Hendricks，K.N.，K.L.B.，E.D.，A.D.，P.S.C.，J.H.，S.Mittman，N.M.，P.D.，W.C.，I.M.，S.Mariathasan，D.S.S.，R.M.，E.Y.C.，R.J.J.和N.S.P.是罗氏/基因泰克的员工和股东。M、 J.宣布研究资金（支付给机构）来自AbbVie，Acerta，Adaptimmune，Amgen，Apexigen，Arcus Biosciences，Array BioPharma，ArriVent BioPharma，Artios Pharma，AstraZeneca，Atreca，BeiGene，BerGenBio，BioAtla，Black Diamond，勃林格殷格翰，百时美施贵宝，Calithera Biosciences，Carisma Therapeutics，Checkpoint Therapeutics，希望之城国家医学中心，Corvus Pharmaceuticals，Curis，CytomX，Daiichi Sankyo，Dracen Pharmaceuticals，Dynavax，Lilly，Eikon Therapeutics，Elicio Therapeutics，EMD Serono，EQRx，Erasca，Exelixis，Fate Therapeutics，Genentech/Roche，Genmab，Genocea Biosciences，GlaxoSmithKline，Gritstone Oncology，Guardant Health，Harpoon，Helsinn Healthcare SA，恒瑞治疗，Hutchison MediPharma，IDEAYA Biosciences，IGM Biosciences，Immunitas Therapeutics，Immunocore，Incyte，Janssen，Jounce Therapeutics，Kadmon Pharmaceuticals，Kartos Therapeutics，LockBody Therapeutics，Loxo Oncology，Lycera，Memorial Sloan Kettering，Merck，Merus，Mirati Therapeutics，Mythic Therapeutics，Neoimune Tech，Neovia Oncology，Novartis，Numab Therapeutics，Nuvalent，OncoMed Pharmaceutic，PMV制药、Rain Therapeutics、RasCal Therapeutics、Regeneron Pharmaceuticals、Relay Therapeutics、Revolution Medicines、Ribon Therapeutics、Rubius Therapeutics、赛诺菲、七和八生物制药/小鸟生物制药、Shattuck Labs、Silicon Therapeutics、Stem CentRx、Syndax Pharmaceuticals、泰和肿瘤学、武田制药、Tarveda、TCR2 Therapeutics、T。

Peer review

同行评审

Peer review information

同行评审信息

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

《自然》杂志感谢克里斯汀·鲍肯（KristenPauken）和另一位匿名审稿人为这项工作的同行评议做出的贡献。

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 Intratumoural myeloid and Treg cell content correlates with tiragolumab plus atezolizumab outcome but not placebo plus atezolizumab.a, Forest plot comparing tiragolumab plus atezolizumab versus placebo plus atezolizumab in patients with tumours expressing high or low gene levels (cutoff by median expression) of CD274, TIGIT, CD226, and PVR in CITYSCAPE.

Additional informationPublisher的注释Springer Nature在已发布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肿瘤内髓样和Treg细胞含量与tiragolumab加atezolizumab结果相关，但与安慰剂加atezolizumab无关。a，比较tiragolumab加atezolizumab与安慰剂加atezolizumab在表达CD274，TIGIT，CD226的高或低基因水平（中位表达截止值）的肿瘤患者中的森林图，和城市景观中的PVR。

Hazard ratio and 95% confidence interval were determined using univariate Cox model. The dots represent the hazard ratio and the horizontal bars the 95% confidence interval. b–e, Kaplan–Meier curves comparing PFS in patients with tumours enriched (solid lines) or not enriched (dashed lines) for TAMs (b), Tregs (c), CD16-high monocytes (d), and CD8 + T effector cells (T-eff) (e).

使用单变量Cox模型确定风险比和95%置信区间。点代表风险比，水平条代表95%置信区间。b–e，Kaplan–Meier曲线比较TAM（b），Tregs（c），CD16高单核细胞（d）和CD8肿瘤富集（实线）或未富集（虚线）患者的PFS + T效应细胞（T-eff）（e）。

Enrichment or not was determined by the median cell type signature score cutoffs. f, g, Kaplan–Meier curves comparing the PFS (f) and OS (g) in PD-L1-positive patients from the phase 3 NSCLC OAK study who received atezolizumab monotherapy and had tumours enriched for TAMs. h, i, Kaplan–Meier curves comparing the PFS (h) and OS (i) in PD-L1-positive patients from the phase 3 NSCLC OAK study who received atezolizumab monotherapy and had tumours enriched for Tregs.

富集与否由中位细胞类型特征评分截止值决定。f、 g，Kaplan-Meier曲线比较了接受atezolizumab单药治疗且肿瘤富含TAM的3期NSCLC OAK研究中PD-L1阳性患者的PFS（f）和OS（g）。h、 i，Kaplan-Meier曲线比较了接受atezolizumab单药治疗且肿瘤富含Tregs的3期NSCLC OAK研究中PD-L1阳性患者的PFS（h）和OS（i）。

f-i, Hazard ratio and 95% confidence interval were determined using univariate Cox model, and P values were estimated using the log-rank test.Extended Data Fig. 2 Correlation of bulk RNA-seq-based cell type signature scores with multiplex immunofluorescence.a, b, Correlation of TAM signature with CD68+ cells by mIF (a) and Treg signature with FoxP3+ cells by mIF (b).

使用单变量Cox模型确定f-i，风险比和95%置信区间，并使用对数秩检验估计P值。扩展数据图2基于大量RNA-seq的细胞类型特征评分与多重免疫荧光的相关性。a，b，mIF（a）的TAM特征与CD68+细胞的相关性和mIF（b）的Treg特征与FoxP3+细胞的相关性。

Two-tailed Pear.

双尾梨。

Nature (2024). https://doi.org/10.1038/s41586-024-07121-9Download citationReceived: 27 January 2022Accepted: 26 January 2024Published: 28 February 2024DOI: https://doi.org/10.1038/s41586-024-07121-9Share 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/s41586-024-07121-9Download引文收到日期：2022年1月27日接受日期：2024年1月26日发布日期：2024年2月28日OI：https://doi.org/10.1038/s41586-024-07121-9Share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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