AbstractTCF1high progenitor CD8+ T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo.

摘要TCF1高祖细胞CD8+T细胞介导免疫治疗的功效；然而，控制其产生和维持的机制知之甚少。在这里，我们表明，通过删除丙酮酸激酶肌肉2（PKM2）靶向糖酵解导致戊糖磷酸途径（PPP）活性升高，导致TCF1高祖细胞耗竭样表型富集，并增加对体内PD-1阻断的反应性。

PKM2KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-13C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells toward a TCF1high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8+ T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids.

通过1,2-13C葡萄糖碳示踪测定，PKM2KO CD8+T细胞显示糖酵解通量降低，糖酵解中间体和PPP代谢物的积累以及PPP循环增加。没有急性糖酵解损伤的PPP的小分子激动作用使CD8+T细胞向TCF1高群体倾斜，产生了独特的转录景观，并且激动剂处理的CD8+T细胞的过继转移与PD-1阻断相结合增强了小鼠的肿瘤控制，并促进了患者来源的肿瘤类器官中的肿瘤杀伤。

Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy..

我们的研究表明，一种新的代谢重编程有助于祖细胞样T细胞状态促进免疫治疗效果。。

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Fig. 1: A genetic screen targeting glycolytic enzymes identifies PKM as a potential regulator of T cell differentiation.Fig. 2: PKM2 is upregulated upon T cell activation in vitro and in vivo, and its deletion results in a less effector-differentiated phenotype.Fig. 3: Loss of PKM2 results in a progenitor-exhausted-like phenotype in CD8+ T cells in NSCLC.Fig.

图1：靶向糖酵解酶的遗传筛选将PKM鉴定为T细胞分化的潜在调节剂。图2:PKM2在体外和体内T细胞活化后上调，其缺失导致效应分化程度较低的表型。图3:PKM2的缺失导致NSCLC中CD8+T细胞的祖细胞耗尽样表型。图。

4: Loss of PKM2 results in a progenitor-exhausted-like phenotype in CD8+ T cells in melanoma.Fig. 5: PKM2 deletion generates T cells with progenitor signatures which enhance the efficacy of PD-1 checkpoint blockade.Fig. 6: PKM2 deletion in T cells results in decreased glycolytic flux and increased pentose phosphate pathway activity.Fig.

4： PKM2的缺失导致黑色素瘤中CD8+T细胞的祖细胞耗竭样表型。图5:PKM2缺失产生具有祖细胞特征的T细胞，其增强PD-1检查点阻断的功效。。图。

7: Pentose phosphate pathway agonism in T cells generates a progenitor phenotype distinct from that induced by hexokinase blockade.Fig. 8: Pentose phosphate pathway agonism results in tumor control in murine and human model systems..

7： T细胞中的戊糖磷酸途径激动作用产生不同于己糖激酶阻断诱导的祖细胞表型。图8：戊糖磷酸途径激动作用导致小鼠和人类模型系统中的肿瘤控制。。

Data availability

数据可用性

Source data for graphically presented data have been provided as Source Data files. Critical analysis outputs and metabolomic and carbon-tracing profiling data have been provided in the Supplementary Tables, with all other data supporting the findings available from the corresponding author on reasonable request.

图形显示数据的源数据已作为源数据文件提供。补充表中提供了关键分析输出以及代谢组学和碳追踪分析数据，所有其他数据支持通讯作者在合理要求下提供的发现。

All other reagents are available either commercially or from the corresponding author on reasonable request. RNA sequencing data are available in the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/gds). Associated accession numbers are: nontreated bulk RNA sequencing, GSE218141; anti-PD-1 bulk RNA sequencing, GSE114300 (ref.

所有其他试剂均可在商业上或根据合理要求从通讯作者处获得。RNA测序数据可在Gene Expression Omnibus中获得(http://www.ncbi.nlm.nih.gov/gds)。相关的登录号是：未处理的大量RNA测序，GSE218141；抗PD-1大量RNA测序，GSE114300（参考文献）。

8); bulk RNA sequencing of isolated adoptively co-transferred TILs, GSE216675; and bulk RNA sequencing of TCF1 reporter eGFP+ and eGFP− T cells from in vitro co-culture and metabolic manipulation, GSE238203. Mouse reference genomes are also available with the following NCBI RefSeq assembly numbers: mm9, GCF_000001635.18; GRCm38, GCF_000001635.20; and GRCm39, GCF_000001635.27.

8） ；分离的过继共转移TIL GSE216675的大量RNA测序；以及来自体外共培养和代谢操作的TCF1报告基因eGFP+和eGFP-T细胞的大量RNA测序，GSE238203。小鼠参考基因组也具有以下NCBI RefSeq装配号：mm9，GCF\U 000001635.18；；和GRCm39，GCF\U 000001635.27。

Source data are provided with this paper..

。。

Code availability

代码可用性

Code for analysis of glycolytic screen data and RNA sequencing data were generated in R using field-standard previously reported packages and indicated parameters, which are described in the Methods and with the relevant source publications cited where appropriate. R code used in this manuscript is available on reasonable request from the corresponding author.

糖酵解筛选数据和RNA测序数据的分析代码是使用先前报道的现场标准软件包和指示参数在R中生成的，这些参数在方法中进行了描述，并在适当的情况下引用了相关的源出版物。本手稿中使用的R代码可根据通讯作者的合理要求获得。

Parameters and relevant filters for Partek Flow analyses, IPA and MetaboAnalyst analyses are described in the appropriate Methods sections..

Partek流量分析，IPA和MetaboAnalyst分析的参数和相关过滤器在适当的方法部分中进行了描述。。

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Download referencesAcknowledgementsWe thank J. Xiang of the Genomics Resources Core Facility, J. McCormick, T. Baumgartner and P. Byrne of the Flow Cytometry Core Facility, K. Rhee of the Department of Microbiology and Immunology and G. Zhang of the Proteomics and Metabolomics Core Facility for their professional advice and technical expertise with RNA sequencing, FACS and steady-state and carbon-tracing metabolomics experiments.

下载参考文献致谢我们感谢基因组学资源核心设施的J.Xiang，流式细胞术核心设施的J.McCormick，T.Baumgartner和P.Byrne，微生物学和免疫学系的K.Rhee以及蛋白质组学和代谢组学核心设施的G.Zhang在RNA测序，FACS以及稳态和碳追踪代谢组学实验方面的专业建议和技术专业知识。

We thank A. Schietinger for helpful discussions and critical manuscript review. We thank S. B. Lee for animal colony management. We thank A. Irizarry for critical support in optimizing the PDTO platform. G.J.M. was supported by postdoctoral fellowships of National Cancer Institute T32 CA203702 and the National Center For Advancing Translational Sciences of the National Institutes of Health under award number KL2-TR-002385.

我们感谢A.Schietinger的有益讨论和批判性稿件审查。我们感谢S.B.Lee的动物群落管理。我们感谢A.Irizarry在优化PDTO平台方面提供的关键支持。G、 J.M.获得了美国国家癌症研究所T32 CA203702和美国国立卫生研究院国家转化科学促进中心的博士后奖学金，奖项编号为KL2-TR-002385。

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported by funds from The Neuberger Berman Foundation Lung Cancer Research Center; a generous gift from Jay and Vicky Furman; and generous funds donated by patients in the Division of Thoracic Surgery to N.K.A.

内容完全由作者负责，不一定代表美国国立卫生研究院的官方观点。这项工作也得到了纽伯格伯曼基金会肺癌研究中心的资助；杰伊和维姬·弗曼的慷慨礼物；以及胸外科患者向N.K.A.捐赠的慷慨资金。

The funding organizations played no role in experimental design, data analysis or manuscript preparation.Author informationAuthor notesDiamile A. TavarezPresent address: Regeneron Pharmaceuticals, Tarrytown, NY, USAEnrique PodazaPresent address: Gritstone Bio, Boston, MA, USAMichael J. P. CrowleyPresent address: SalioGen Therapeutics, Lexington, MA, USAM.

资助组织在实验设计，数据分析或稿件准备方面没有发挥任何作用。作者信息作者注释Diamile A.Tavarez目前的地址：Regeneron Pharmaceuticals，Tarrytown，NY，USAERIQUE PODAZA目前的地址：Grittone Bio，Boston，MA，USAMACHAEL J.P.Crowley目前的地址：SalioGen Therapeutics，Lexington，MA，USAM。

Laura MartinPresent address: Altos Labs, Redwood City, CA, USAThese authors contributed equally: Yi Ban, Diamile A. Tavarez, Liron Yoffe, Enrique Podaza.Authors and AffiliationsDepartme.

劳拉·马丁（LauraMartinPresent）地址：美国加利福尼亚州红木市阿尔托斯实验室（Altos Labs），这些作者做出了同样的贡献：伊班（Yi Ban），戴米尔·塔瓦雷斯（DiamileA.Tavarez），利隆·约菲（LironYoffe），恩里克·波达扎（EnriquePodaza）。作者和附属机构。

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PubMed Google ScholarContributionsG.J.M. and V.M. conceptualized the project and designed the experiments. G.J.M. performed the mouse experiments with assistance from Y.B., D.A.T., Y.H. and M.T.M. G.J.M., E.P., M.L.M. and O.E. designed the immunocompetent human PDTO platform and E.P.

PubMed谷歌学术贡献。J、 M.和V.M.将该项目概念化并设计了实验。G、 J.M.在Y.B.，D.A.T.，Y.H.和M.T.M.G.J.M.，E.P.，M.L.M.和O.E.的帮助下进行了小鼠实验。设计了免疫活性人PDTO平台和E.P。

performed experiments with the samples from patients. Y.B., D.A.T., Y.H., M.T.M. and D.G. provided suggestions and technical support for experiments. D.G. aided in sorting cells. M.J.P.C. and L.Y. provided code and support for RNA sequencing analyses. T.A.S. provided technical support for Seahorse analyses.

用患者的样本进行了实验。Y、 B.，D.A.T.，Y.H.，M.T.M.和D.G.为实验提供了建议和技术支持。D、 G.有助于分选细胞。M、 J.P.C.和L.Y.为RNA测序分析提供了代码和支持。T、 A.S.为海马分析提供了技术支持。

J.R.C.-R. and T.E.M. provided guidance on analysis and interpretation of metabolic data generated in the study. J.R.C.-R. provided guidance on interpretation of T cell differentiation data generated in the study. V.M. and N.K.A. provided project oversight and support. G.J.M. wrote the manuscript. G.J.M.

J、 R.C.-R.和T.E.M.为研究中产生的代谢数据的分析和解释提供了指导。J、 R.C.-R.为解释研究中产生的T细胞分化数据提供了指导。五、 M.和N.K.A.提供了项目监督和支持。G、 J.M.写了手稿。G、 J.M。

and V.M. edited the manuscript with input from other authors. All authors discussed the results and conclusions drawn from the studies.Corresponding authorCorrespondence to.

V.M.在其他作者的意见下编辑了手稿。所有作者都讨论了从研究中得出的结果和结论。对应作者对应。

Vivek Mittal.Ethics declarations

维韦克·米塔尔。道德宣言

Competing interests

相互竞争的利益

J.R.C.-R. is a scientific consultant for NextRNA Therapeutics and Autoimmunity Biologic Solutions and holds patents on IRE1α modulation for the treatment of disease. O.E. is supported by Janssen, J&J, Astra-Zeneca, Volastra and Eli Lilly research grants. He is a scientific advisor and equity holder in Freenome, Owkin, Volastra Therapeutics and One Three Biotech and a paid scientific advisor to Champions Oncology and Pionyr Immunotherapeutics.

J、 R.C.-R.是NextRNA治疗和自身免疫生物解决方案的科学顾问，拥有IRE1α调节治疗疾病的专利。O、 E.得到了杨森、强生、阿斯特拉·捷利康、沃拉斯特拉和礼来研究基金的支持。他是Freenome，Owkin，Volastra Therapeutics和One Three Biotech的科学顾问和股东，也是Champions Oncology和Pionyr Immunotherapeutics的付费科学顾问。

The other authors declare no competing interests..

其他作者声明没有利益冲突。。

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Nature Immunology thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: S. Houston in collaboration with the Nature Immunology team.

Nature Immunology感谢匿名审稿人对这项工作的同行评议做出的贡献。主要处理编辑：S.Houston与Nature Immunology团队合作。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended dataExtended Data Fig. 1 Glycolysis signatures are enriched in tumor-infiltrating T cells from larger tumors, both in mice treated with IgG control and in mice treated with anti-PD-1.a, Gene set enrichment analysis using the KEGG Glycolysis / Gluconeogenesis dataset for differences in glycolytic gene signatures in tumor-infiltrating CD8 + T cells between: anti-PD-1-treated progressing (Group 3) and anti-PD-1-treated regressing (Group 2) tumors at early timepoints; anti-PD-1-treated progressing (Group 6) and anti-PD-1-treated regressing (Group 4) tumors at later timepoints; and anti-PD-1-treated progressing (Group 6) and anti-PD-1-treated partially regressing (Group 5) tumors at later timepoints.

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。扩展数据扩展数据图1在用IgG对照处理的小鼠和用抗PD-1处理的小鼠中，糖酵解特征在来自较大肿瘤的肿瘤浸润性T细胞中富集。a，使用KEGG糖酵解/糖异生数据集进行基因集富集分析用于早期时间点抗PD-1处理的进展（组3）和抗PD-1处理的消退（组2）肿瘤之间肿瘤浸润性CD8+T细胞中糖酵解基因特征的差异；在较晚的时间点，抗PD-1治疗的进展（第6组）和抗PD-1治疗的消退（第4组）肿瘤；和抗PD-1治疗的进展（第6组）和抗PD-1治疗的部分消退（第5组）肿瘤在稍后的时间点。

b, Heatmap showing normalized expression of selected genes from the KEGG Glycolysis / Gluconeogenesis dataset across groups. Numbers: (a-b) n = 3-8 biological replicates per group. Statistics: (a) GSEA by fgsea package in R.Extended Data Fig. 2 Expression and presentation of Ova257-264 in ova-GFP-expressing cell lines, characterization of antigen-specific T cell phenotypes elicited by in vitro co-culture with antigen-expressing tumor cells, and pyruvate kinase isoform expression characteristics in CD8 + T cells.a,b, Contour plots displaying PD-L1 and MHC I-Ova257-264 (left) and GFP and MHC I-Ova257-264 (right) in HKP1-ova-GFP cells (a) or B16F10-ova-GFP cells (b) with (blue) or without (red) overnight stimulation with 20 ng/mL IFNγ.

b、 热图显示来自KEGG糖酵解/糖异生数据集的选定基因在各组之间的标准化表达。。统计学：（a）R中fgsea包装的GSEA。扩展数据图2 Ova257-264在表达ova-GFP的细胞系中的表达和呈递，通过与表达抗原的肿瘤细胞体外共培养引发的抗原特异性T细胞表型的表征，以及CD8+T细胞中丙酮酸激酶同种型的表达特征。a，b，在HKP1 ova-GFP细胞（a）或B16F10 ova-GFP细胞（b）中显示PD-L1和MHC I-Ova257-264（左）以及GFP和MHC I-Ova257-264（右）的等高线图用（蓝色）或不用（红色）过夜刺激20 ng/mL IFNγ。

c, Schematic for co-culture experiment. d, Histograms of IFNγ and GzmB expression on days 3-10 of the experiment. e, Mean fluorescence intensities of checkpoint proteins evaluated in naï.

c、 共培养实验示意图。d、 实验第3-10天IFNγ和GzmB表达的直方图。e、 在naï中评估的检查点蛋白的平均荧光强度。

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