Review
Immunology
Roy A. Mariuzza, Daichao Wu, Brian G. Pierce
Summary: This review summarizes recent studies on the structural and biophysical aspects of T cell receptor (TCR) recognition of shared cancer neoantigens derived from oncogenes. The findings reveal the correlation between different mutations and the antigen presentation, and discuss the potential of TCR-mimic antibodies as an alternative to TCRs for targeting cancer neoantigens. Additionally, the review highlights recent computational advances and the significance of structural information in predicting neoepitope immunogenicity.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Multidisciplinary Sciences
Kimberly G. Laffey, Robert J. Stiles, Melissa J. Ludescher, Tessa R. Davis, Shariq S. Khwaja, Richard J. Bram, Peter J. Wettstein, Venkataraman Ramachandran, Christopher A. Parks, Edwin E. Reyes, Alejandro Ferrer, Jenna M. Canfield, Cory E. Johnson, Richard D. Hammer, Diana Gil, Adam G. Schrum
Summary: During normal T cell development, a low-frequency population of early all TCR+ DN cells is present, which requires CD3δ for their generation/detection. These cells can respond to MHC and display coreceptor-independent MHC reactivity. It has been observed that these cells are susceptible to T-ALL transformation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Meagan R. Rollins, Jackson F. Raynor, Ebony A. Miller, Jonah Z. Butler, Ellen J. Spartz, Walker S. Lahr, Yun You, Adam L. Burrack, Branden S. Moriarity, Beau R. Webber, Ingunn M. Stromnes
Summary: TCR transgenic mice are a valuable tool for studying antigen-specific immune responses. The TRex methodology, which integrates TCRs specific to the self/tumor antigen mesothelin (Msln) into the Trac locus, is shown to improve the functional sensitivity of lower affinity TCRs and confer resistance to T cell functional loss. By comparing TCRs with the same specificity but different affinity, the Trac-targeted TCRs are shown to have increased avidity over transgenic TCRs while preserving physiological T cell development. Overall, the TRex methodology is an advanced tool for studying physiological antigen-specific T cell behavior.
NATURE COMMUNICATIONS
(2023)
Review
Medicine, General & Internal
Ella S. Atsavapranee, Margaret M. Billingsley, Michael J. Mitchell
Summary: Genetic engineering has transformed cancer immunotherapy by modifying primary T cells to enhance their therapeutic potential, with studies and clinical trials supporting the effectiveness of this approach.
Article
Immunology
Mikiya Tsunoda, Hiroyasu Aoki, Haruka Shimizu, Shigeyuki Shichino, Kouji Matsushima, Satoshi Ueha
Summary: Temporal analysis of T cell receptor (TCR) repertoire is important for monitoring changes in antigen-specific T cells in cancer patients. However, lack of experimental models for temporal analysis within a homogeneous population limits understanding of the relationship between TCR repertoire changes and antitumor responses. Bilateral tumor model showed highly similar T-cell clones in bilateral tumors and different patterns in draining lymph nodes, suggesting independent induction of tumor-reactive T cell clones in each lymph node.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Immunology
Yifan Xu, Jin Jiang, Yutong Wang, Wei Wang, Haokun Li, Wenyu Lai, Zhipeng Zhou, Wei Zhu, Zheng Xiang, Zhiming Wang, Zhe Zhu, Lingfeng Yu, Xiaolan Huang, Hua Zheng, Sha Wu
Summary: Gynecologic malignancies are leading causes of death among women worldwide, and adoptive T cell therapy using engineered T cells has shown promising efficacy in treating tumors. Ongoing research is driving the application of this therapy in the treatment of gynecologic malignancies.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Immunology
Rosa A. van Amerongen, Sander Tuit, Anne K. Wouters, Marian van de Meent, Sterre L. Siekman, Miranda H. Meeuwsen, Tassilo L. A. Wachsmann, Dennis F. G. Remst, Renate S. Hagedoorn, Dirk M. van der Steen, Arnoud H. de Ru, Els M. E. Verdegaal, Peter A. van Veelen, J. H. Frederik Falkenburg, Mirjam H. M. Heemskerk
Summary: Recurrent disease is common in ovarian cancer patients. Adoptive T-cell therapies using T-cell receptors (TCRs) targeting tumor-associated antigens (TAAs) show promise in treating less-immunogenic 'cold' ovarian tumors. This study identified PRAME, CTCFL, and CLDN6 as strictly tumor-specific TAAs with high expression in ovarian cancer and low expression in healthy tissues. High-avidity T-cell clones recognizing peptides derived from these TAAs were isolated and showed potent antitumor reactivity in vitro and in vivo. These findings provide valuable candidates for the treatment of ovarian cancer and other PRAME or CTCFL expressing cancers.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Pharmacology & Pharmacy
Yuanyuan Liu, Shuai Chen, Simon Liu, Kevin L. Wallace, Marietta Zille, Jiewen Zhang, Jian Wang, Chao Jiang
Summary: Stroke is a severe and life-threatening disease that requires more research on new treatment strategies. Infiltrated T lymphocytes play a crucial role in post-stroke inflammation and have conflicting roles as therapeutic targets. Understanding the mechanisms of the adaptive immune response associated with T lymphocytes is essential for developing effective treatments.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Immunology
Jiaqi Xia, Peng Bai, Weiliang Fan, Qiming Li, Yongzheng Li, Dehe Wang, Lei Yin, Yu Zhou
Summary: T-cell recognition of cancer neoepitopes derived from somatic mutations can trigger tumor regression. Establishing a database for sharing validated cancer neoantigens is beneficial for precise cancer immunotherapy, while predicting neoepitopes in silico is important but laborious. NEPdb is a database containing over 17,000 human immunogenic neoantigens and ineffective neoepitopes, as well as pan-cancer level predicted HLA-I neoepitopes derived from shared cancer somatic mutations. This database enhances the efficiency of neoantigen-based cancer studies and treatments with its well-designed search engine and visualization modes.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Anastasiia A. Kalinina, Ludmila M. Khromykh, Dmitry B. Kazansky
Summary: Gene modification of T cells with tumor antigen-specific T cell receptors (TCRs) is a milestone in personalized cancer immunotherapy. Some receptors possess chain centricity, where one hemi-chain TCR dominates antigen recognition and dictates its specificity, but research in this area is still relatively limited.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Lucia Mazzotti, Anna Gaimari, Sara Bravaccini, Roberta Maltoni, Claudio Cerchione, Manel Juan, Europa Azucena-Gonzalez Navarro, Anna Pasetto, Daniela Nascimento Silva, Valentina Ancarani, Vittorio Sambri, Luana Calabro, Giovanni Martinelli, Massimiliano Mazza
Summary: The immune system is influenced by individual characteristics and exposures. Pathological conditions depend on the response of the immune system and TCR repertoire sequencing can provide insights into its behavior. Understanding the technology and applications of TCR repertoire sequencing is crucial for researchers.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Ping Wen, Wei Wu, Feifan Wang, Hanqi Zheng, Ziyan Liao, Jiaqi Shi, Chaojie Zhu, Peng Zhao, Hao Cheng, Hongjun Li, Zhen Gu
Summary: Adoptive cell therapy (ACT) using allogeneic or autologous immune cells shows promise in targeted cancer therapy, but its efficacy against solid tumors is limited. This review summarizes various devices for cell delivery and discusses the perspectives and challenges of using these devices for cancer immunotherapy.
JOURNAL OF CONTROLLED RELEASE
(2023)
Review
Immunology
Anna Pasetto, Yong-Chen Lu
Summary: T cells are essential in immune responses and cancer immunotherapy. Single-cell sequencing techniques have enabled scientists to study T cells at a deeper level, including T-cell receptor and transcriptome analysis. These techniques also aid in the identification of T-cell neoantigens, advancing T-cell mediated cancer therapy.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Cell Biology
Xuejin Ou, Qizhi Ma, Wei Yin, Xuelei Ma, Zhiyao He
Summary: Immunotherapy has shown great promise in cancer therapy, with the CRISPR/Cas9 system providing a foundation for innovative research and treatment. CRISPR/Cas9 can be used to construct CAR-T cells and TCR-T cells, inhibit immune checkpoint signaling pathways, and screen novel cancer immunotherapy targets.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Jun Chang
Summary: The MHC multimer technology has revolutionized the quantification and analysis of antigen-specific T cells, especially CD8 T cells. Its application has expanded to various T cell types and functions, including cell sorting and single-cell classification through DNA barcodes.
MOLECULES AND CELLS
(2021)
Review
Immunology
Mirjam E. Hoekstra, Saskia V. Vijver, Ton N. Schumacher
Summary: In the tumor micro-environment, activated CD8(+) T cells secrete cytokines like IFN gamma, TNF alpha, and IL-2, but the understanding of how these cytokines are sensed by other cells is limited. This review focuses on the behavior of these T-cell-secreted cytokines in the TME, proposing a model that suggests variations in cytokine secretion, half-life, clearance, and binding sculpt the tissue response to T-cell activation in cancer.
CURRENT OPINION IN IMMUNOLOGY
(2021)
Article
Multidisciplinary Sciences
Anastasia Gangaev, Steven L. C. Ketelaars, Olga I. Isaeva, Sanne Patiwael, Anna Dopler, Kelly Hoefakker, Sara De Biasi, Lara Gibellini, Cristina Mussini, Giovanni Guaraldi, Massimo Girardis, Cami M. P. Talavera Ormeno, Paul J. M. Hekking, Neubury M. Lardy, Mireille Toebes, Robert Balderas, Ton N. Schumacher, Huib Ovaa, Andrea Cossarizza, Pia Kvistborg
Summary: This study identified a range of SARS-CoV-2 CD8(+) T cell responses across COVID-19 patients, including an epitope from ORF1ab with immunodominant features. The specific CD8(+) T cell responses can still be detectable up to 5 months after recovery from critical and severe disease, converting from dysfunctional effector cells to functional memory cells during convalescence.
NATURE COMMUNICATIONS
(2021)
Review
Immunology
Ali Can Sahillioglu, Ton N. Schumacher
Summary: The development of genetic safety switches to control the activity of T cells in vivo has become an active research field. These switches can reversibly control cell products through the supply or removal of small molecules, protein-based regulators, or physical stimuli. Various mechanistic classes of genetic safety switches are discussed in this review.
CURRENT OPINION IN IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Anne M. van der Leun, Mirjam E. Hoekstra, Luuk Reinalda, Colinda L. G. J. Scheele, Mireille Toebes, Michel J. van de Graaff, Hanjie Li, Akhiad Bercovich, Yaniv Lubling, Eyal David, Daniela S. Thommen, Amos Tanay, Jacco van Rheenen, Ido Amit, Sander van Kasteren, Ton N. Schumacher
Summary: The study introduces a photocage-based technology that allows isolation and in-depth analysis of live cells from complex ex vivo systems, including primary human tissues. By using nanobodies and a highly sensitive 4-nitrophenyl(benzofuran) cage, high-resolution photo-uncaging of different cell types in areas of interest is achieved.
NATURE CHEMICAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Paula Voabil, Marjolein de Bruijn, Lisanne M. Roelofsen, Sanne H. Hendriks, Simone Brokamp, Marlous van den Braber, Annegien Broeks, Joyce Sanders, Petra Herzig, Alfred Zippelius, Christian U. Blank, Koen J. Hartemink, Kim Monkhorst, John B. A. G. Haanen, Ton N. Schumacher, Daniela S. Thommen
Summary: A study using patient-derived tumor fragments as an ex vivo platform showed that the reactivation of tumor-infiltrating immune cells after PD-1 blockade could predict clinical outcomes. Tumor-resident T cells were identified as crucial in the immunological response, and a subgroup of tumors was found to be unresponsive to PD-1 blockade. Additionally, the presence of tertiary lymphoid structures in baseline tumors correlated with the capacity for intratumoral immune cell reactivation.
Article
Oncology
Victoria S. Pelly, Agrin Moeini, Lisanne M. Roelofsen, Eduardo Bonavita, Charlotte R. Bell, Colin Hutton, Adrian Blanco-Gomez, Antonia Banyard, Christian P. Bromley, Eimear Flanagan, Shih-Chieh Chiang, Claus Jorgensen, Ton N. Schumacher, Daniela S. Thommen, Santiago Zelenay
Summary: By profiling mice and human tumors, this study identifies mechanisms by which anti-inflammatory drugs rapidly alter the tumor immune landscape to enhance tumor immunogenicity and responses to immune checkpoint inhibitors.
Article
Oncology
Ali Can Sahillioglu, Mireille Toebes, Georgi Apriamashvili, Raquel Gomez, Ton N. Schumacher
Summary: A small-molecule responsive genetic safety switch has been developed to restore or block the activity of T cells by controlling drug administration, providing a new approach for tumor therapy with reversibility and titratability. This switch can be combined with various T cell receptors, making it a universal and versatile platform for regulating the activity of cell products.
CANCER IMMUNOLOGY RESEARCH
(2021)
Article
Oncology
Noor Alida Maria Bakker, Jossie Rotman, Marc van Beurden, Henry J. M. A. Zijlmans, Maartje van Ruiten, Sanne Samuels, Bastiaan Nuijen, Jos Beijnen, Karin De Visser, John Haanen, Ton Schumacher, Tanja de Gruijl, Ekaterina S. Jordanova, Gemma G. Kenter, Joost H. van den Berg, Nienke E. van Trommel
Summary: The HPV-16 E6/E7 DNA tattoo vaccination is an effective and safe treatment strategy for patients with uVIN, with HPV-specific T-cell responses being associated with clinical benefit.
JOURNAL FOR IMMUNOTHERAPY OF CANCER
(2021)
Meeting Abstract
Oncology
W. Scheper, C. Cattaneo, J. Urbanus, T. Battaglia, J. B. A. G. Haanen, E. E. Voest, T. N. Schumacher
ANNALS OF ONCOLOGY
(2021)
Article
Biotechnology & Applied Microbiology
Muhammad Ali, Eirini Giannakopoulou, Yingqian Li, Madeleine Lehander, Stina Virding Culleton, Weiwen Yang, Cathrine Knetter, Mete Can Odabasi, Ravi Chand Bollineni, Xinbo Yang, Zsofia Foldvari, Maxi-Lu Boschen, Eli Taraldsrud, Erlend Stronen, Mireille Toebes, Amy Hillen, Stefania Mazzi, Arnoud H. de Ru, George M. C. Janssen, Arne Kolstad, Geir Erland Tjonnfjord, Benedicte A. Lie, Marieke Griffioen, Soren Lehmann, Liv Toril Osnes, Jochen Buechner, K. Christopher Garcia, Ton N. Schumacher, Peter A. van Veelen, Matthias Leisegang, Sten Eirik W. Jacobsen, Petter Woll, Johanna Olweus
Summary: T cells modified with TCRs targeting TdT can specifically eliminate acute lymphoblastic leukemia cells while sparing normal lymphocytes. TdT is highly expressed in cancer cells but transiently expressed in normal cells, thus limiting the toxicity of T cell targeting TdT.
NATURE BIOTECHNOLOGY
(2022)
Review
Multidisciplinary Sciences
Ton N. Schumacher, Daniela S. Thommen
Summary: This article discusses the current knowledge on TLSs in cancer, focusing on the drivers of TLS formation, the function and contribution of TLSs to the antitumor immune response, and the potential of TLSs as therapeutic targets in human cancers.
Article
Oncology
Hsuan-An Chen, Yu-Jui Ho, Riccardo Mezzadra, Jose M. Adrover, Ryan Smolkin, Changyu Zhu, Katharina Woess, Nicholas Bernstein, Georgia Schmitt, Linda Fong, Wei Luan, Alexandra Wuest, Sha Tian, Xiang Li, Caroline Broderick, Ronald C. Hendrickson, Mikala Egeblad, Zhenghao Chen, Direna Alonso-Curbelo, Scott W. Lowe
Summary: Cellular senescence involves a stable cell-cycle arrest coupled to a secretory program that stimulates immune clearance of senescent cells. Senescent cells also remodel the cell-surface proteome to alter how tumor cells sense environmental factors, such as type II interferon. This study demonstrates that senescent cells have an enhanced ability to both send and receive environmental signals, which is required for their effective immune surveillance.
Article
Oncology
Rona Yaeger, Riccardo Mezzadra, Jenna Sinopoli, Yu Bian, Michelangelo Marasco, Esther Kaplun, Yijun Gao, HuiYong Zhao, Arnaud Da Cruz Paula, Yingjie Zhu, Almudena Chaves Perez, Kalyani Chadalavada, Edison Tse, Sudhir Chowdhry, Sydney Bowker, Qing Chang, Besnik Qeriqi, Britta Weigelt, Gouri J. Nanjangud, Michael F. Berger, Hirak Der-Torossian, Kenna Anderes, Nicholas D. Socci, Jinru Shia, Yonina R. Murciano-Goroff, Bob Li, James G. Christensen, Jorge S. Reis-Filho, David B. Solit, Elisa de Stanchina, Scott W. Lowe, Neal Rosen, Sandra Misale
Summary: Combining KRASG12C and EGFR inhibitors is an effective treatment for colorectal cancer. However, secondary resistance can reduce its efficacy. Our study found that resistance alterations preventing inhibition of ERK signaling are detected at a low frequency, except for KRASG12C amplification, which increases over time. Upon drug withdrawal, resistant cells undergo senescence, but mTOR signaling remains elevated. Targeting the senescence response may be a potential therapeutic vulnerability to overcome acquired resistance.
Article
Medicine, Research & Experimental
Arnab Ghosh, Judith Michels, Riccardo Mezzadra, Divya Venkatesh, Lauren Dong, Ricardo Gomez, Fadi Samaan, Yu-Jui Ho, Luis Felipe Campesato, Levi Mangarin, John Fak, Nathan Suek, Aliya Holland, Cailian Liu, Mohsen Abu-Akeel, Yonina Bykov, Hong Zhong, Kelly Fitzgerald, Sadna Budhu, Andrew Chow, Roberta Zappasodi, Katherine S. Panageas, Olivier de Henau, Marcus Ruscetti, Scott W. Lowe, Taha Merghoub, Jedd D. Wolchok
Summary: This study demonstrates that enhancing p53 signaling in the tumor microenvironment can boost antitumor T cell immunity and improve the effectiveness of immune checkpoint blockade. Increase of p53 expression in tumor-associated macrophages leads to their senescence and suppression of proteins associated with M2 polarization. These findings suggest that reprogramming the tumor microenvironment through increased p53 expression in macrophages enhances the response to immune checkpoint blockade.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Review
Immunology
Lianne Kok, David Masopust, Ton N. Schumacher
Summary: CD8(+) tissue resident memory T cells are crucial for immune defence against pathogens and malignancies. While it was previously believed that these cells formed locally within inflamed tissue, emerging evidence suggests the existence of circulating T-RM cell precursors. This review discusses the formation of T-RM cells and the signals within the lymphoid compartment that influence their lineage decisions.
NATURE REVIEWS IMMUNOLOGY
(2022)