海报库PosterKeep
PO.CL01.12 · 临床研究

侵袭性淋巴瘤中与CAR-T治疗临床应答相关的线粒体转录组谱

Mitochondrial transcriptome profiles associated with clinical responses to CAR-T therapy in aggressive lymphoma

编号 1213 展板 14 时间 4/19 02:00–05:00 区域 Section 47 主讲 Jacqueline Turner, MD;PhD
分会场 Spatial Proteomics and Transcriptomics 1
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作者与单位 Authors & Affiliations

Jacqueline Turner1, Panwen Wang2, Patrizia Mondello1, Melinda Tan3, Christoph Schaefers1, Chen Wu4, Andre de Menezes Silva Corraes4, Kevin Regan4, Zuoyi Shao4, Ma Audrey4, Arushi Khurana4, Nora N. Benanni4, Yucai Wang4, Paul Hampel4, Saad J. Kenderian4, Jonas Paludo4, Urshila Durani4, Patrick B. Johnston5, Jose Caetano Villasboas4, Stephen M. Ansell6, Haidong Dong1, Ying Li4, Zeng Hu4, Yi Lin7

1Mayo Clinic College of Medicine and Science, Rochester, MN,2Mayo Clinic, Scottsdale, AZ,3Mayo Clinic Cancer Center Minnesota, Rochester, MN,4Mayo Clinic, Rochester, MN,5Hematology, Mayo Clinic College of Medicine, Rochester, MN,6Assistant Professor, Div. of Hematology, Mayo Clinic College of Medicine, Rochester, MN,7Asst. Professor, Div. of Hemat., Mayo Clinic, Rochester, MN

摘要 Abstract

中文摘要
引言：随着嵌合抗原受体T细胞（CAR-T）治疗的引入，B细胞非霍奇金淋巴瘤（B-NHL）的治疗结局已显著改善。然而，持续的免疫功能障碍和潜在的代谢失调仍是B-NHL实现持久临床应答的主要障碍。我们假设线粒体通路在CAR-T治疗期间介导抗肿瘤免疫中发挥关键作用。 方法：从健康对照（CNTRL，n=5）和接受FDA批准的CAR-T治疗的晚期淋巴瘤（LYM）患者（n=32）中采集外周血单个核细胞。样本在清淋前（BL）、CAR-T扩增峰值（PK）和输注后一个月（M1）采集。使用单细胞RNA测序探究线粒体基因差异表达。样本取自完全缓解>6个月（CR）、原发难治（PD1）或复发（PD2）疾病的LYM患者。 结果：与CNTRL相比，LYM患者表现出细胞色素c氧化酶表达降低。在BL时，CR患者相较于PD1和PD2在所有T细胞亚群中表现出更广泛的线粒体差异基因表达，并显示更高的MT-ATP-6、MT-ATP-8和MT-CO3表达。CAR-T输注后，全局线粒体基因表达在各患者中增加，对应于CD8效应T细胞（Tem肿瘤循环）和活化的外周记忆T细胞（Tpm）的扩增。某些线粒体基因，如MT-CO1，在LYM患者的外周和中央记忆T细胞（Tpm、Tcm）中于BL、PK和M1持久表达。在PK时，细胞色素c氧化酶和ATP合酶基因在CR的Tpm和Tcm中上调。在M1时，MT-ATP-6、MT-ATP-8、MT-CO3在CR患者的CD8记忆前体效应T细胞（MPEC）中相较于PD1和PD2均显著上调。虽然CR和PD2患者在M1时临床上均表现为应答，但CR样本在各T细胞亚群（CD8 MPEC、Tpm、Tcm）中维持显著更高的MT-ATP-8表达，相较于PD2（p值0.008；<0.0001；<0.0001）。 结论：我们报告了LYM中CAR-T治疗引起的免疫代谢的时间性转变。临床应答者表现出持续的线粒体活性，其特征为CD8 MPEC中ATP合酶及Tpm和Tcm中细胞色素c氧化酶的持久表达。总之，线粒体程序可能区分有效与功能障碍的T细胞，并识别治疗开发的靶点。
查看英文原文 English abstract
Introduction: Therapeutic outcomes in B-cell non-Hodgkin's lymphoma (B-NHL) have substantially improved with the introduction of chimeric antigen receptor T-cell (CAR-T) therapy. Yet, persistent immune dysfunction and underlying metabolic dysregulation remain major obstacles to achieving durable clinical responses in B-NHL. We hypothesize that mitochondrial pathways play a critical role in mediating anti-tumor immunity during CAR-T therapy. Methods: Peripheral blood mononuclear cells were collected from healthy controls (CNTRL, n=5) and patients with advanced stage lymphoma (LYM) who received FDA approved CAR-T (n=32). Samples were collected before lymphodepletion (BL), at peak CAR-T expansion (PK) and one-month post-infusion (M1). Single-cell RNA sequencing was used to interrogate differential mitochondrial gene expression. Samples were obtained from LYM patients with complete remission for > 6 months (CR), primary refractory (PD1), or relapsed (PD2) disease. Results: Compared to CNTRLs, LYM patients exhibited reduced expression of cytochrome c oxidase. At BL, CR patients demonstrated broader mitochondrial differential gene expression across all T-cell subsets relative to PD1 and PD2 and showed higher expression of MT-ATP-6 , MT-ATP-8 , and MT-CO3 . Following CAR-T infusion, global mitochondrial gene expression increased across patients corresponding with expansion of CD8 effector T cells (Tem tumor circulating) and activated peripheral memory T cells (Tpm). Certain mitochondrial genes, such as MT-CO1 , were durably expressed across LYM patients at BL, PK, and M1 in peripheral and central memory T cells (Tpm, Tcm). At PK, cytochrome c oxidase and ATP synthase genes were upregulated in CR Tpm and Tcm. At M1, MT-ATP-6 , MT-ATP-8 , MT-CO3 were significantly upregulated in CD8 memory precursor effector T-cells (MPECs) of CR patients compared to both PD1 and PD2. While CR and PD2 patients appeared clinically responsive at M1, CR samples maintained significantly higher MT-ATP-8 expression across T cell subsets (CD8 MPECS, Tpm, Tcm) compared to PD2 (p values 0.008; <0.0001; <0.0001). Conclusions: We report a temporal shift in immunometabolism with CAR-T therapy in LYM. Clinical responders exhibited sustained mitochondrial activity characterized by persistent expression of ATP synthase in CD8 MPECs and cytochrome c oxidase in Tpm and Tcm. In sum, mitochondrial programming may distinguish effective versus dysfunctional T cells and identify targets for therapeutic development.
利益披露 Disclosure
J. Turner, Blood Cell Therapeutics Other, Consultant. P. Wang, None.. P. Mondello, None.. C. Schaefers, None.. C. Wu, None.. A. de Menezes Silva Corraes, None.. K. Regan, None.. Z. Shao, None.. M. Audrey, None.. A. Khurana, None. N. N. Benanni, Vyriad, Consultancy Other, Consultant. Acrotech Biopharma Other, Consultant. Astellas Pharma Other, Consultant. Affimed Therapeutics Other, Consultant. Y. Wang, Kite Other, Consultant. Genentech ). Loxo/Eli Lily ), Consultant. Merck ). Morphosys ). Incyte ), Other, Consultant. Novartis ). Genmab ), Other, Consultant. Abbvie ), Other, Consultant. InnoCare ), Other, Consultant. P. Hampel, AstraZeneca ). BeOne Medicines Ltd ). AbbVie Other, Consultant. S. J. Kenderian, Humanigen ), Other, Consultant. MorphoSys ). Novartis Other Securities, ), Patent, Other, Consultant. Chymal Therapeutics Stock, Patent. BMS ), Other, Consultant. Gilead ), Other, Consultant. Carisma Other, Consultant. Immix Bio Patent. Kite ), Other, Consultant. Juno/BMS ), Other, Consultant. Humanigen/Taran Patent. LifEngine Animal Health Laboratories Inc ). Sunesis/Viracta ). Lentigen ). Luminary Other, Consultant. MustangBio Patent. Capstan Bio Other, Consultant. Tolero ). J. Paludo, Biofourmis ). AstraZeneca ), Other, Honoraria. AbbVie Other, Honoraria. Karyopharm ). U. Durani, None.. P. B. Johnston, None. J. Villasboas, Bristol Myers Squibb/Celgene ). CRISPR ). TG Therapeutics Other, consultant. Kite Pharma ). Regeneron Pharmaceuticals, Inc ), Other, Consultant. Epizyme ). Enterome ). Curio Science Other, Consultant. Aptose Biosciences ). Kite/Gilead Other, Consultant. Genentech, Inc./F. Hoffman La-Roche Ltd ). S. M. Ansell, Pfizer ). Regeneron ). AstraZeneca ). Bristol Myers Squibb ). Step Pharma ). Affimed ). Takeda ). ADC Therapeutics ). H. Dong, None.. Y. Li, None.. Z. Hu, None. Y. Lin, Bristol-Myers Squibb ), Other, Consultant. Caribou Biosciences Other, Consultant. Kite/Gilead Other, Consultant. Pfizer Other, Consultant. Janssen ), Other, Consultant. Genentech Other, Consultant. Regeneron Other, Consultant. Nektar Other, Consultant. Tessera Other, Consultant. Sanofi Other, Consultant. NexImmune Other, Consultant. Adicet Bio Other, Consultant. Chimeric Therapeutics Other, Consultant. Fosun Kite Other, Consultant. Legend Biotech Other, Consultant. Vineti Other, Consultant.

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