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Curated Papers > In recent years, high-impact research on "single-cell sequencing" (IF ≥ 30, last 5 years)

Deciphering and advancing CAR T-cell therapy with single-cell sequencing technologies. ​

Literature Information ​

DOI10.1186/s12943-023-01783-1
PMID37149643
JournalMolecular cancer
Impact Factor33.9
JCR QuartileQ1
Publication Year2023
Times Cited18
KeywordsBiology, CAR T-cell, Mechanisms, Single-cell sequencing technologies, Strategies
Literature TypeJournal Article, Review, Research Support, Non-U.S. Gov't
ISSN1476-4598
Pages80
Issue22(1)
AuthorsShengkang Huang, Xinyu Wang, Yu Wang, Yajing Wang, Chenglong Fang, Yazhuo Wang, Sifei Chen, Runkai Chen, Tao Lei, Yuchen Zhang, Xinjie Xu, Yuhua Li

TL;DR ​

This review discusses the advancements in chimeric antigen receptor (CAR) T-cell therapy and the role of single-cell sequencing technologies in addressing the challenges associated with its clinical application, particularly in understanding cellular heterogeneity and molecular patterns. It emphasizes the need for a multi-omics research approach to enhance CAR T-cell therapy's effectiveness and guide future research directions.

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Biology · CAR T-cell · Mechanisms · Single-cell sequencing technologies · Strategies

Abstract ​

Chimeric antigen receptor (CAR) T-cell therapy has made remarkable progress in cancer immunotherapy, but several challenges with unclear mechanisms hinder its wide clinical application. Single-cell sequencing technologies, with the powerful unbiased analysis of cellular heterogeneity and molecular patterns at unprecedented resolution, have greatly advanced our understanding of immunology and oncology. In this review, we summarize the recent applications of single-cell sequencing technologies in CAR T-cell therapy, including the biological characteristics, the latest mechanisms of clinical response and adverse events, promising strategies that contribute to the development of CAR T-cell therapy and CAR target selection. Generally, we propose a multi-omics research mode to guide potential future research on CAR T-cell therapy.

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Primary Questions Addressed ​

  1. What are the specific biological characteristics of CAR T-cells that can be revealed through single-cell sequencing?
  2. How do single-cell sequencing technologies improve our understanding of adverse events in CAR T-cell therapy?
  3. What are the latest findings regarding the mechanisms of clinical response in CAR T-cell therapy as analyzed by single-cell sequencing?
  4. In what ways can multi-omics approaches enhance the development of CAR T-cell therapy?
  5. What strategies have shown promise in CAR target selection based on insights gained from single-cell sequencing?

Key Findings ​

Research Background and Purpose ​

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized cancer immunotherapy, particularly for hematological malignancies. Despite its success, challenges such as high costs, limited accessibility, resistance, and adverse events hinder its broader application. This review focuses on how single-cell sequencing technologies can enhance the understanding and development of CAR T-cell therapy by providing insights into cellular heterogeneity, molecular mechanisms, and strategies for target selection.

Main Methods/Materials/Experimental Design ​

The review employs a multi-omics approach, integrating various single-cell sequencing technologies to analyze CAR T-cell therapy. The key technologies discussed include:

  • Single-cell RNA sequencing (scRNA-seq): To analyze gene expression profiles and cellular heterogeneity.
  • Single-cell T-cell receptor sequencing (scTCR-seq): To characterize T-cell clonotypic diversity and functional phenotypes.
  • Single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq): To map open chromatin regions and identify transcription factor binding sites.
  • Cytometry by time-of-flight (CyTOF): For high-dimensional analysis of protein expression.
  • Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq): To assess both transcriptome and surface protein expression simultaneously.
  • Secretome proteomics: To analyze cytokine secretion profiles.

The methodologies are illustrated in the following flowchart:

Mermaid diagram

Key Results and Findings ​

  1. Heterogeneity of CAR T-cells: Different CAR T-cell products show varied efficacy based on CAR structure, T cell subtype, and manufacturing processes. For example, CAR T-cells with different costimulatory domains (CD28 vs. 4-1BB) exhibit distinct transcriptional profiles affecting their persistence and effectiveness.

  2. Single-cell Analysis Insights: scRNA-seq has revealed that the presence of Treg cells and the metabolic state of CAR T-cells influence treatment outcomes. Increased expression of exhaustion markers correlates with poor responses, while memory-like CD8+ T-cells are associated with better outcomes.

  3. Mechanisms of Resistance and Relapse: The review identifies key factors contributing to primary resistance (e.g., exhaustion markers like TIGIT) and relapse mechanisms, including the emergence of antigen-negative tumor cells and the role of the tumor microenvironment.

  4. Adverse Events: The review highlights the roles of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), identifying monocytes as significant sources of IL-6 during CRS.

  5. Combination Therapies: Strategies combining CAR T-cell therapy with other treatments (e.g., chemotherapy, STING agonists) have shown promise in enhancing therapeutic efficacy.

Main Conclusions/Significance/Innovation ​

The integration of single-cell sequencing technologies into CAR T-cell therapy research offers a comprehensive understanding of cellular dynamics, heterogeneity, and mechanisms of action. This multi-omics approach can guide the design of next-generation CAR T-cells, optimize target selection, and improve patient outcomes. The review emphasizes the need for continued innovation in CAR T-cell therapy, including engineering strategies and combination therapies, to address existing challenges.

Research Limitations and Future Directions ​

Despite the advancements, challenges remain, including the high cost of single-cell sequencing technologies and the need for standardized protocols. Future research should focus on developing comprehensive atlases of normal and diseased tissues to facilitate target validation and improve the understanding of on-target, off-tumor effects. Additionally, further exploration of CAR T-cell dynamics in diverse patient populations is essential for optimizing therapy and personalizing treatment strategies.

References ​

  1. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. - Sara Ghorashian;Anne Marijn Kramer;Shimobi Onuoha;Gary Wright;Jack Bartram;Rachel Richardson;Sarah J Albon;Joan Casanovas-Company;Fernanda Castro;Bilyana Popova;Krystle Villanueva;Jenny Yeung;Winston Vetharoy;Aleks Guvenel;Patrycja A Wawrzyniecka;Leila Mekkaoui;Gordon Weng-Kit Cheung;Danielle Pinner;Jan Chu;Giovanna Lucchini;Juliana Silva;Oana Ciocarlie;Arina Lazareva;Sarah Inglott;Kimberly C Gilmour;Gulrukh Ahsan;Mathieu Ferrari;Somayya Manzoor;Kim Champion;Tony Brooks;Andre Lopes;Allan Hackshaw;Farzin Farzaneh;Robert Chiesa;Kanchan Rao;Denise Bonney;Sujith Samarasinghe;Nicholas Goulden;Ajay Vora;Paul Veys;Rachael Hough;Robert Wynn;Martin A Pule;Persis J Amrolia - Nature medicine (2019)
  2. IFNγ Is Critical for CAR T Cell-Mediated Myeloid Activation and Induction of Endogenous Immunity. - Darya Alizadeh;Robyn A Wong;Sharareh Gholamin;Madeleine Maker;Maryam Aftabizadeh;Xin Yang;Joseph R Pecoraro;John D Jeppson;Dongrui Wang;Brenda Aguilar;Renate Starr;Claire B Larmonier;Nicolas Larmonier;Min-Hsuan Chen;Xiwei Wu;Antoni Ribas;Behnam Badie;Stephen J Forman;Christine E Brown - Cancer discovery (2021)
  3. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. - Shannon L Maude;Theodore W Laetsch;Jochen Buechner;Susana Rives;Michael Boyer;Henrique Bittencourt;Peter Bader;Michael R Verneris;Heather E Stefanski;Gary D Myers;Muna Qayed;Barbara De Moerloose;Hidefumi Hiramatsu;Krysta Schlis;Kara L Davis;Paul L Martin;Eneida R Nemecek;Gregory A Yanik;Christina Peters;Andre Baruchel;Nicolas Boissel;Francoise Mechinaud;Adriana Balduzzi;Joerg Krueger;Carl H June;Bruce L Levine;Patricia Wood;Tetiana Taran;Mimi Leung;Karen T Mueller;Yiyun Zhang;Kapildeb Sen;David Lebwohl;Michael A Pulsipher;Stephan A Grupp - The New England journal of medicine (2018)
  4. Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. - Qing Deng;Guangchun Han;Nahum Puebla-Osorio;Man Chun John Ma;Paolo Strati;Beth Chasen;Enyu Dai;Minghao Dang;Neeraj Jain;Haopeng Yang;Yuanxin Wang;Shaojun Zhang;Ruiping Wang;Runzhe Chen;Jordan Showell;Sreejoyee Ghosh;Sridevi Patchva;Qi Zhang;Ryan Sun;Frederick Hagemeister;Luis Fayad;Felipe Samaniego;Hans C Lee;Loretta J Nastoupil;Nathan Fowler;R Eric Davis;Jason Westin;Sattva S Neelapu;Linghua Wang;Michael R Green - Nature medicine (2020)
  5. Dynamic chromatin regulatory landscape of human CAR T cell exhaustion. - David G Gennert;Rachel C Lynn;Jeff M Granja;Evan W Weber;Maxwell R Mumbach;Yang Zhao;Zhana Duren;Elena Sotillo;William J Greenleaf;Wing H Wong;Ansuman T Satpathy;Crystal L Mackall;Howard Y Chang - Proceedings of the National Academy of Sciences of the United States of America (2021)
  6. Mechanisms underlying CD19-positive ALL relapse after anti-CD19 CAR T cell therapy and associated strategies. - Yuru Nie;Weiqing Lu;Daiyu Chen;Huilin Tu;Zhenling Guo;Xuan Zhou;Meifang Li;Sanfang Tu;Yuhua Li - Biomarker research (2020)
  7. Common Trajectories of Highly Effective CD19-Specific CAR T Cells Identified by Endogenous T-cell Receptor Lineages. - Taylor L Wilson;Hyunjin Kim;Ching-Heng Chou;Deanna Langfitt;Robert C Mettelman;Anastasia A Minervina;E Kaitlynn Allen;Jean-Yves Métais;Mikhail V Pogorelyy;Janice M Riberdy;M Paulina Velasquez;Pratibha Kottapalli;Sanchit Trivedi;Scott R Olsen;Timothy Lockey;Catherine Willis;Michael M Meagher;Brandon M Triplett;Aimee C Talleur;Stephen Gottschalk;Jeremy Chase Crawford;Paul G Thomas - Cancer discovery (2022)
  8. The triumphs and limitations of computational methods for scRNA-seq. - Peter V Kharchenko - Nature methods (2021)
  9. Immunotherapy of cancer in single-cell RNA sequencing era: A precision medicine perspective. - Nafiseh Erfanian;Afshin Derakhshani;Saeed Nasseri;Mohammad Fereidouni;Behzad Baradaran;Neda Jalili Tabrizi;Oronzo Brunetti;Renato Bernardini;Nicola Silvestris;Hossein Safarpour - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (2022)
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Literatures Citing This Work ​

  1. Revolutionizing cancer immunotherapy in solid tumor: CAR engineering and single-cell sequencing insights. - Zuhui Pu;Tony Bowei Wang;Lisha Mou - Frontiers in immunology (2023)
  2. Harnessing the Transcriptional Signatures of CAR-T-Cells and Leukemia/Lymphoma Using Single-Cell Sequencing Technologies. - Yu-Mei Liao;Shih-Hsien Hsu;Shyh-Shin Chiou - International journal of molecular sciences (2024)
  3. Neural Network-Based Filter Design for Compressive Raman Classification of Cells. - Stefan Semrau - Journal of chemical information and modeling (2024)
  4. Single-cell RNA sequencing in ovarian cancer: revealing new perspectives in the tumor microenvironment. - Qiannan Zhao;Huaming Shao;Tianmei Zhang - American journal of translational research (2024)
  5. Role of N6-methyladenosine RNA modification in cancer. - Yi Qu;Nannan Gao;Shengwei Zhang;Limin Gao;Bing He;Chao Wang;Chunli Gong;Qiuyue Shi;Zhibin Li;Shiming Yang;Yufeng Xiao - MedComm (2024)
  6. Recover then aggregate: unified cross-modal deep clustering with global structural information for single-cell data. - Ziyi Wang;Peng Luo;Mingming Xiao;Boyang Wang;Tianyu Liu;Xiangyu Sun - Briefings in bioinformatics (2024)
  7. Leveraging CRISPR gene editing technology to optimize the efficacy, safety and accessibility of CAR T-cell therapy. - Tao Lei;Yazhuo Wang;Yuchen Zhang;Yufei Yang;Jiaying Cao;Jiansong Huang;Jiali Chen;Huajing Chen;Jiayi Zhang;Luzheng Wang;Xinjie Xu;Robert Peter Gale;Liang Wang - Leukemia (2024)
  8. Immunofluorescence-Verified Sphingolipid Signatures Indicate Improved Prognosis in Liver Cancer Patients. - Lujuan Pan;Huijuan Huang;Pengpeng Zhang;Hua Li;Libai Lu;Mingwei Wei;Pin Zheng;Qi Wang;Junyu Guo;Yueqiu Qin - Journal of Cancer (2024)
  9. Advances and applications in single-cell and spatial genomics. - Jingjing Wang;Fang Ye;Haoxi Chai;Yujia Jiang;Teng Wang;Xia Ran;Qimin Xia;Ziye Xu;Yuting Fu;Guodong Zhang;Hanyu Wu;Guoji Guo;Hongshan Guo;Yijun Ruan;Yongcheng Wang;Dong Xing;Xun Xu;Zemin Zhang - Science China. Life sciences (2025)
  10. Role of CD4+ T cells in cancer immunity: a single-cell sequencing exploration of tumor microenvironment. - Qi An;Li Duan;Yuanyuan Wang;Fuxin Wang;Xiang Liu;Chao Liu;Qinyong Hu - Journal of translational medicine (2025)

... (8 more literatures)

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