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【导读】 新辅助免疫化疗（nICT）极大地改变了可手术食管鳞状细胞癌（ESCC）的治疗格局，但影响肿瘤对nICT反应的因素尚不清楚。在这项研究中，使用单细胞RNA测序与T细胞受体测序配对，团队分析了接受nICT治疗的ESCC患者的组织，并表征了肿瘤微环境的背景。 2024年10月22日，中国医学科学院肿瘤医院高树庚团队在期刊《Nature Communications》上发表了题为“Single-cell sequencing reveals immune features of treatment response to neoadjuvant immunochemotherapy in esophageal squamous cell carcinoma”的研究论文。 研究结果强调了CXCL13作为辅助治疗提高免疫治疗疗效的潜力， 确定了LRRC15 CAFs和SPP1巨噬细胞的富集是免疫治疗耐药的关键标志物。这些发现为未来研究改善ESCC免疫治疗反应的最佳策略，提供了理论依据。 https://www.nature.com/articles/s41467-024-52977-0 关于食管癌 01 食管癌（EC）是全球第七大最常见的恶性肿瘤，也是癌症死亡的第六大原因。食管鳞状细胞癌（ESCC）几乎占EC病例的90%，本质上是高度恶性的，在东亚尤其普遍。由于其症状不明显，大多数ESCC患者在晚期被诊断出来，导致5年总生存率低于20%。对于可切除的局部晚期ESCC患者，新辅助放化疗（nCRT）后进行食管切除术是目前的标准护理治疗，与单独手术相比，生存率更高。 新辅助免疫治疗，尤其是免疫检查点阻断（ICB），显示出卓越的临床益处，并改变了各种实体瘤的治疗模式。对于晚期转移性ESCC，免疫化疗已被美国食品和药品监督管理局批准为一线治疗。新辅助免疫化疗（nICT）已显示出对可手术的局部晚期ESCC的有希望的益处，在不增加手术并发症发生率的情况下，实现高达50%的pCR率。 这项研究将scRNA-seq与scTCR-seq配对，以研究18名接受nICT治疗的ESCC患者的细胞生物学和动力学。研究结果表明，CD8 Tex-CXCL13在应答者的治疗前肿瘤中显著富集，并且在相应的治疗后样本中，显示出更明显的祖细胞耗竭表型。这项研究阐明了对nICT治疗的不同反应的免疫特征， 这对增强ESCC中的抗PD-1疗效具有潜在意义。 SPP1巨噬细胞和高表达SPP1的肿瘤细胞，是治疗后ESCC免疫治疗耐药的标志物 02 与接受nICT治疗的ESCC反应者相比，团队观察到Macro-SPP1、Macro-EREG和Macro-STMN1在治疗后无反应者中显著富集。scCODA分析还显示，Macro-SPP1、Macro-EREG和Macro-STMN1的浸润水平相对较高。而亚群Macro-SLC40A1则显示出相反的分布。这些证据证明，SPP1巨噬细胞可以促进肿瘤进展，介导TME重塑并限制对PD-L1阻断的反应。一致地，Macro-SPP1上调的DEGs显示与TME重塑相关的信号通路显著富集，包括细胞因子/趋化因子介导的信号通路和白细胞迁移。细胞间相互作用分析，揭示了Macro-SPP1与治疗后反应者和非反应者中的各种T细胞簇之间，存在不同的通信网。 在nICT治疗期间，反应者中Macro-SPP1的浸润水平显著下降；而与治疗后无反应者相比，Macro-SPP1的浸润水平显著降低。在治疗后的ESCC中，发现Macro-SPP1和CD4 Treg-TNFRSF4之间存在显著的正相关，但在治疗前样本中则没有，这表明两个簇之间的相互作用，可能是由免疫化疗诱导的。这些发现揭示了Macro-SPP1是ESCC中免疫治疗耐药性的关键标志物，这可能通过细胞间相互作用激活Tregs并抑制CTL。 凋亡信号通路的调节和对氧化/化学应激的反应显著富集，表明对细胞毒性T细胞和铂类化疗药物诱导的细胞凋亡耐药。与反应者相比，团队还发现SPP1在治疗后无反应者的残留肿瘤细胞中高表达。预计无反应者的残留ESCC肿瘤细胞，与CD8 Tn、CD8 Tex和CD8 Tem细胞的相互作用潜力增强。在TCGA-ESCA队列中，SPP1的高表达水平，成为重要的预后危险因素。在ESCC-nICT队列中，治疗后样本的SPP1表达，也是免疫化疗反应的重要预测因子。总之， SPP1巨噬细胞和高度表达SPP1的肿瘤细胞，是治疗后ESCC对免疫治疗耐药的标志物。 SPP1除了是免疫治疗反应的关键预测因子外，还与TME内的细胞毒性CD8 T细胞相互作用，最终限制抗肿瘤免疫。 SPP1作为免疫治疗耐药性的重要标志物。 总结 03 主要发现： 1. CD8 T细胞（Tex）的终末耗竭和CD4调节性T细胞（Tregs）引起的高耐受性，是ESCC对免疫治疗耐药的主要因素； 2. 无反应者治疗后CD8 Tex-CXCL13浸润水平显著升高，且这些细胞对PD-1/PD-L1抑制剂的反应性有限； 3. 无反应者中CD4 Treg-TNFRSF4显著增加，与免疫抑制性特征相关，表明消除Treg障碍可能提高nICT疗效。 CXCL13的角色： 1. CD8 Tex-CXCL13在反应者中的预处理样本中深入渗透，可能作为nICT治疗效果的预测因子； 2. CXCL13的基线富集可能通过促进肿瘤相关三级淋巴结构（TLS）的形成和成熟，使肿瘤对免疫治疗敏感； 3. rmCXCL13能显著增强抗PD-1治疗在ESCC小鼠模型中的疗效。 CAFs和巨噬细胞的作用： 1. 治疗无反应者中升高的肿瘤相关成纤维细胞（tCAF-MMP11）与免疫治疗耐药性密切相关，并与CD4 Treg-TNFRSF4细胞比例正相关； 2. LRRC15 CAFs可能通过招募和激活免疫抑制性CD4 Tregs，来限制免疫治疗效果； 3. SPP1巨噬细胞和高度表达SPP1的肿瘤细胞是ESCC中免疫治疗耐药的关键标志物，可能通过靶向CD44抑制CD8 T细胞活化。 参考资料： 1.Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer J. Clin. 71, 209–249 (2021). 2.Chen, W. et al. Cancer statistics in China, 2015. CA A Cancer J. Clin. 66, 115–132 (2016). 【关于投稿】 转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！ 转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。 热门推荐活动 点击免费报名 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会 🕓 上海｜11月21日-24日 ▶ 第七届上海国际肿瘤内科学论坛 🕓 全国｜2024年12月-2025年03月 ▶ 中国转化医学产业大会 🕓 上海｜2025年02月28日-03月01日 ▶ 第四届长三角单细胞组学技术应用论坛暨空间组学前沿论坛 点击对应文字 查看详情

FLORHAM PARK, N.J.--( BUSINESS WIRE )--Shionogi Inc., the United States subsidiary of Shionogi & Co., Ltd., (Head Office: Osaka, Japan; Chief Executive Officer: Isao Teshirogi, Ph.D.) will have 22 scientific presentations across the company’s infectious disease portfolio at IDWeek 2024 (October 16-19, 2024) in Los Angeles, California. Key among Shionogi’s 13 data presentations for Fetroja® (cefiderocol) will be a new real-world evidence study including approximately 1,000 patients treated with cefiderocol from across the U.S. and Europe. This trial, known as PROVE, is the largest study to evaluate cefiderocol use in hospitalized patients with serious Gram-negative infections, the majority of whom were resistant to carbapenem antibiotics. Notably, Shionogi will have two oral presentations featuring nonclinical data evaluating cefiderocol activity against some of the most difficult-to-treat bacterial strains that were resistant to antibiotics, alone and in combination with xeruborbactam, an investigational beta-lactamase inhibitor that became part of the Shionogi pipeline with the acquisition of Qpex Biopharma, Inc. (hereafter “Qpex”) by Shionogi Inc. in 2023. “Here in the U.S., a core focus of our work includes continuing to evaluate real-world outcomes associated with the use of our antibiotic for the treatment of certain Gram-negative infections and ensuring we’re meeting the educational and practical needs of our customers and their patients,” said Nate McCutcheon, President and Chief Executive Officer, Shionogi Inc. “We’re proud to make this important medication available and we also recognize that ongoing innovation is critical in infectious disease. That’s why we recently announced plans to expand our global infectious disease and antimicrobial research operations in the U.S. through Qpex with the establishment of our first U.S.-based discovery laboratory in San Diego.” Shionogi is honored to announce that Michael N. Dudley, PharmD, President and CEO of Qpex will deliver the keynote address at the Society of Infectious Diseases Pharmacists (SIDP) Annual Meeting, taking place in conjunction with IDWeek. In addition to numerous scientific presentations at IDWeek, Shionogi will once again enable the infectious disease community to join the fight and take a stand against the global public health threat of antimicrobial resistance (AMR) with a new version of its award-winning AMR Warrior experience. All visitors to Shionogi’s Booth #322 will have the opportunity to create their own AMR Warrior and use the image to spread awareness amongst their own networks and communities. Shionogi’s presence at IDWeek will also include a sponsored Learning Lounge on Friday, October 18, at 10:15 AM PT, featuring Thomas Lodise, PharmD, PhD, Professor at the Albany College of Pharmacy and Health Sciences, entitled “Fetroja® (cefiderocol): An Overview of In Vitro, Clinical, and Real-world Data.” Summary of Presentations Cefiderocol data presentations at IDWeek will include: Oral #513: Cefiderocol Retains in vitro Activity Against Enterobacterales Non-Susceptible to beta-lactam-beta-lactamase Inhibitor Combinations Poster #650: In vitro Activity of Cefiderocol and Comparator Agents Against Global Enterobacterales Isolates from Hospitalized Patients with Pneumonia Collected as Part of the SENTRY Surveillance Program (2020-2022) Poster #1099: Correlation Analysis of Cefiderocol in vitro Activity and in vivo Efficacy Against Acinetobacter baumannii Strains with Difficult-to-Read MIC Endpoints Poster #1100: Activity of Cefiderocol and Comparator Agents Against Global Isolates of Stenotrophomonas maltophilia from the SENTRY Antimicrobial Surveillance Program (2020–2023) Poster #1360: Activity of Cefiderocol Against Carbapenem Non-susceptible Enterobacterales, Including Molecularly Characterized Multidrug-resistant Clinical Isolates, Causing Infections in United States Hospitals (2020–2023) Poster #1361: Cefiderocol Activity Against Pseudomonas aeruginosa , Including Resistant Subsets and Isolates Carrying Carbapenemase beta-lactamase Genes, from United States Hospitals (2020–2023) Poster #1362: Cefiderocol Activity Against Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex, Including Molecularly Characterized Clinical Isolates, Causing Infections in United States Hospitals (2020–2023) Poster #1363: Cefiderocol Activity Against Clinical Enterobacterales Isolates Carrying Metallo-beta-lactamase Genes in United States and European Hospitals (2020–2023) Poster #1364: Cefiderocol Activity Against Pseudomonas aeruginosa Clinical Isolates Carrying Metallo-beta-lactamase Genes in United States and European Hospitals (2020–2023) Poster #1472: Cefiderocol Remains Highly Active Against Carbapenemase-Producing Enterobacterales Poster #1475: Real-World Effectiveness and Safety of Cefiderocol in the Treatment of Patients with Serious Gram-negative Bacterial Infections: Results of the PROVE Chart Review Study Poster #1484: In vitro Activity of Cefiderocol and Comparator Agents Against Non-fermentative Gram-negative Bacilli Isolated from Patients Hospitalized with Pneumonia as part of the SENTRY Global Surveillance Program (2020-2022) Poster #1530: Evaluation of Phenotypic Cross-Resistance Between Cefiderocol and beta-lactam/beta-lactamase Inhibitor Combinations Against Pseudomonas aeruginosa Isolates from US Medical Centers Xeruborbactam data presentations at IDWeek will include: Oral #514: The Impact of Xeruborbactam on in vitro Activity of Cefiderocol Against a Panel of Acinetobacter baumannii Enriched in Isolates with Reduced Cefiderocol Susceptibility Poster #1110: The Impact of Xeruborbactam on in vitro Activity of Cefiderocol Against a Panel of Enterobacterales Enriched with Isolates with Reduced Cefiderocol Susceptibility For Full Prescribing Information for Fetroja® (cefiderocol), including approved Indications and Safety Information, please visit https://www.shionogi.com/content/dam/shionogi/si/products/pdf/fetroja.pdf . Shionogi’s scientific contributions at IDWeek will also include seven poster presentations featuring clinical, nonclinical and real-world evidence from its COVID-19 franchise. For more information, including a complete list of abstracts, please visit https://idweek.org/program/ . IDWeek attendees can learn more about Shionogi at Booth #322. About Shionogi in Infectious Disease Since 1953, Shionogi has been a leader in infectious disease discovery and commercialization. Our R&D story extends beyond antibiotics to include novel medications for HIV and influenza. Today, our global pipeline includes investigational agents developed to address global health challenges including antimicrobial resistance, COVID-19, influenza, rare fungal diseases and respiratory syncytial virus. As part of our commitment to addressing unmet medical needs, Shionogi is partnering with several non-governmental organizations to increase equitable access to our medications worldwide. Shionogi has a landmark license and technology transfer agreement for cefiderocol with Global Antibiotic Research and Development Partnership (GARDP) and a collaboration agreement with the Clinton Health Access Initiative (CHAI) to transform the landscape of access to antibiotics in many low-income countries, most lower middle- and upper middle-income countries, and select high-income countries. About Shionogi Inc. Shionogi Inc. is a U.S. subsidiary of Shionogi & Co., Ltd., a Japanese research-driven pharmaceutical company committed to developing innovative medicines that address unmet medical needs for people worldwide. Since 1878, we have been harnessing the full potential of science to address global health challenges. Over the past six decades, we have discovered several novel antibiotics and medications for HIV and influenza. Today, we’ve focused on developing antibiotics for infections due to serious Gram-negative bacteria and antivirals for COVID-19. In addition to infectious disease, we are also advancing rare disease clinical programs in Fragile X syndrome and Pompe disease. Learn more at Shionogi.com . About Qpex Biopharma Inc., a Shionogi Group Company Qpex Biopharma, Inc. is a resistance-focused infectious disease company on a mission to make both a dramatic and sustainable improvement in patient care across both inpatient and outpatient settings. Advancing a robust portfolio of best-in-class, clinical-stage products, the company’s lead program is based on xeruborbactam, an investigational beta-lactamase inhibitor discovered by Qpex scientists. For more information, please visit www.qpexbio.com . Forward-Looking Statements This announcement contains forward-looking statements. These statements are based on expectations in light of the information currently available, assumptions that are subject to risks and uncertainties which could cause actual results to differ materially from these statements. Risks and uncertainties include general domestic and international economic conditions such as general industry and market conditions, and changes of interest rate and currency exchange rate. These risks and uncertainties particularly apply with respect to product-related forward-looking statements. Product risks and uncertainties include, but are not limited to, completion and discontinuation of clinical trials; obtaining regulatory approvals; claims and concerns about product safety and efficacy; technological advances; adverse outcome of important litigation; domestic and foreign healthcare reforms and changes of laws and regulations. Also for existing products, there are manufacturing and marketing risks, which include, but are not limited to, inability to build production capacity to meet demand, lack of availability of raw materials and entry of competitive products. The company disclaims any intention or obligation to update or revise any forward-looking statements whether as a result of new information, future events or otherwise.

引言 CD8+T细胞是抵御感染性疾病和肿瘤的免疫系统关键介质。在遭遇抗原后，T细胞激活并浸润到感染部位。在感染灶处，T细胞实现抵御病原体功能，并产生持久的异质记忆T细胞亚群。尽管一些记忆T细胞 (包括中枢记忆和效应记忆性T细胞，也就是Tcm和Tem，统称Tcirc) 在血液和淋巴系统中循环，但其他记忆T细胞则永久驻留在外周组织和器官中。在不同物种的所有器官中，均发现这些不会进行迁移的组织驻留记忆T (tissue-resident memory T，简称TRM) 细胞【1,2】。 组织微环境、细胞因子暴露、抗原持久性和T细胞受体(TCR)信号强度变化等因素，促使T细胞处于不同效应阶段，最终演化成异质性CD8+T细胞亚群【3-7】。其中一些记忆性CD8+T细胞群表现出不同的干细胞样特性和功能，并提供不同程度的免疫保护。在某些情况下，如慢性感染或肿瘤病灶处，与稳健的记忆T细胞群相比，持续抗原识别诱导的T细胞活化，最终导致其演化为耗竭T细胞 (exhausted T，简称TEX)，表现出功能弱化和抑制受体表达增加。高通量测序技术的引入和迭代，也大幅提升了学界对T细胞演化和异质性相关的转录和表观遗传变化的理解。 通过Tcirc细胞发育过程中DNA甲基化和染色质可及性的动态全基因组测序和分析，证明小鼠和人类中效应T细胞和记忆T细胞命运决定因素的复杂网络。而通过单细胞表观基因组分析，确定了在不同的细胞亚群中，顺式和反式调控元件的变化与基因表达调控息息相关，从而可以实现重塑细胞分化相关轨迹。尽管已经明确Tcirc、TRM和TEX细胞存在异质性，并且这类异质性是由转录谱差异所决定的，但是，不同组织中CD8+T细胞的表观遗传谱变化，仍没有详细研究过。 近日，来自美国斯坦福大学的Ansuman T. Satpathy和澳大利亚墨尔本大学Laura K. Mackay研究组合作在Immunity上发表题为Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation的文章，通过分析来自多个器官的T细胞的染色质可及性变化和基因表达谱演化，揭示了记忆性CD8+T细胞的表观遗传状态，并鉴定了参与T细胞分化的器官特异性调节因子。 记忆性CD8+T细胞库中包含多种具有表型和转录异质性的亚群，它们承载特异的功能和再循环模式。作者在四种不同感染模型中，分离出七种非淋巴器官中的CD8+T细胞，并进行表观遗传谱分析。在急性淋巴细胞性脉络丛脑膜炎病毒 (acute lymphocytic choriomeningitis virus，简称LCMV) 感染过程中，作者观察到肝脏中TRM和Tcirc前体的早期表观遗传分化，并展示出不同的发育轨迹。这种效应细胞命运的早期转移以Fcgr2b可及性和FcgRIIB表达差异为标志，它们可以提升记忆性T细胞前体选择性产生肝脏TRM或Tcirc亚群的能力。 尽管TRM细胞在表观遗传谱上与Tcirc不同，但对从不同器官分离的TRM细胞，利用单细胞转座酶可及染色质可及性测序分析发现，TRM和Tcirc细胞沿着不同的表观遗传轨迹发育。而且，转录因子可以以器官特异性的方式调节TRM细胞的形成。作者还确定了TRM细胞发育的器官特异性转录调控因子，包括FOSB、FOS、FOSL1和BACH2，并定义了跨器官TRM细胞共有的表观遗传特征。此外，对每个器官内TRM细胞的单独分析，揭示了与转录因子保守网络相关的组织内异质性，包括KLF和HIC 元件。 最后，作者还发现在TEX细胞亚群中，终末期TEX 细胞在核心表观遗传特征谱中包含有独特的顺式调控元件可及性。 综上所述，作者检测了小鼠急性和慢性感染后从不同解剖部位分离的CD8+T细胞的转录和染色质可及性变化，通过不同的表观遗传谱定义不同TRM细胞亚群分化，这也是器官特异性表型和转录差异形成的基础。此外，作者还提供了公共基因组浏览器，用于查询CD8效应T细胞和记忆T细胞以及TRM和TEX细胞的染色质可及性谱，以支持未来的研究。 参考文献 1. Masopust, D., and Soerens, A.G. (2019). Tissue-Resident T Cells and Other Resident Leukocytes. Annu. Rev. Immunol. 37, 521–546. 2. Szabo, P.A., Miron, M., and Farber, D.L. (2019). Location, location, loca- tion: Tissue resident memory T cells in mice and humans. Sci. Immunol. 4, 1–12. 3. Christo, S.N., Evrard, M., Park, S.L., Gandolfo, L.C., Burn, T.N., Fonseca, R., Newman, D.M., Alexandre, Y.O., Collins, N., Zamudio, N.M., et al. (2021). Discrete tissue microenvironments instruct diversity in resident memory T cell function and plasticity. Nat. Immunol. 22, 1140–1151. 4. Mackay, L.K., Minnich, M., Kragten, N.A.M., Liao, Y., Nota, B., Seillet, C., Zaid, A., Man, K., Preston, S., Freestone, D., et al. (2016). Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lympho- cytes. Science 352, 459–463. 5. Kumar, B.V., Ma, W., Miron, M., Granot, T., Guyer, R.S., Carpenter, D.J., Senda, T., Sun, X., Ho, S.H., Lerner, H., et al. (2017). Human Tissue- Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites. Cell Rep. 20, 2921–2934. 6. Beura, L.K., Wijeyesinghe, S., Thompson, E.A., Macchietto, M.G., Rosato, P.C., Pierson, M.J., Schenkel, J.M., Mitchell, J.S., Vezys, V., Fife, B.T., et al. (2018). T Cells in Nonlymphoid Tissues Give Rise to Lymph-Node- Resident Memory T Cells. Immunity 48, 327–338.e5. 7. Masopust, D., Choo, D., Vezys, V., Wherry, E.J., Duraiswamy, J., Akondy, R., Wang, J., Casey, K.A., Barber, D.L., Kawamura, K.S., et al. (2010). Dynamic T cell migration program provides resident memory within intes- tinal epithelium. J. Exp. Med. 207, 553–564. https://doi.org/10.1016/j.immuni.2024.06.014 责编|探索君 排版|探索君 文章来源|“BioArt” End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell综述