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Citations to this article

MyD88/CD40 signaling retains CAR T cells in a less differentiated state
Brooke Prinzing, … , Giedre Krenciute, Stephen Gottschalk
Brooke Prinzing, … , Giedre Krenciute, Stephen Gottschalk
Published November 5, 2020
Citation Information: JCI Insight. 2020;5(21):e136093. https://doi.org/10.1172/jci.insight.136093.
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Research Article Immunology Therapeutics Article has an altmetric score of 7

MyD88/CD40 signaling retains CAR T cells in a less differentiated state

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Abstract

Chimeric antigen receptor (CAR) T cell therapy for solid tumors has shown limited efficacy in early-phase clinical studies. The majority of CARs encode CD28 and/or 41BB costimulatory endodomains, and we explored whether MyD88 and CD40 (MC) costimulatory endodomains in CARs could improve their antitumor activity. We generated CD28-, 41BB-, and MC-CAR T cells and demonstrated that MC-CAR T cells have greater proliferative capacity and antitumor activity in repeat stimulation assays and in tumor models in vivo. Transcriptomic analysis revealed that MC-CAR T cells expressed higher levels of MYB and FOXM1, key cell cycle regulators, and were activated at baseline. After stimulation, MC-CAR T cells remained in a less differentiated state than CD28- and 41BB-CAR T cells as judged by low levels of transcription factor TBET and B lymphocyte induced maturation protein 1 expression and lower cytolytic activity in comparison with CD28- and 41BB-CAR T cells. Thus, including MyD88 and CD40 signaling domains in CARs may improve current CAR T cell therapy approaches for solid tumors.

Authors

Brooke Prinzing, Patrick Schreiner, Matthew Bell, Yiping Fan, Giedre Krenciute, Stephen Gottschalk

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Year: 2025 2024 2023 2022 2021 Total
Citations: 5 8 8 9 7 37
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Citations to this article (37)

Title and authors Publication Year
Enhancement of anti‐sarcoma immunity by NK cells engineered with mRNA for expression of a EphA2‐targeted CAR
Lam PY, Omer N, Wong JK, Tu C, Alim L, Rossi GR, Victorova M, Tompkins H, Lin C, Mehdi AM, Choo A, Elliott MR, Coleborn E, Sun J, Mercer T, Vittorio O, Dobson LJ, McLellan AD, Brooks A, Tuong ZK, Cheetham SW, Nicholls W, Souza\u2010Fonseca\u2010Guimaraes F
Clinical and Translational Medicine 2025
Dissecting the role of CAR signaling architectures on T cell activation and persistence using pooled screens and single-cell sequencing
Castellanos-Rueda R, Wang KL, Forster JL, Driessen A, Frank JA, Martínez MR, Reddy ST
Science Advances 2025
Enhancing CAR T-Cell Function with Domains of Innate Immunity Sensors
Mlakar T, Skrbinek M, Fink T, Lainšček D
International Journal of Molecular Sciences 2025
Tonic signaling in CAR-T therapy: the lever long enough to move the planet.
Huang Y, Wang H
Frontiers of medicine 2025
Library-based single-cell analysis of CAR signaling reveals drivers of in vivo persistence
Perez CR, Garmilla A, Nilsson A, Baghdassarian HM, Gordon KS, Lima LG, Smith BE, Maus MV, Lauffenburger DA, Birnbaum ME
Cell systems 2025
Toll-like receptor 4 signaling activation domains promote CAR T cell function against solid tumors
Mikolič V, Pantović-Žalig J, Malenšek Š, Sever M, Lainšček D, Jerala R
2024
Unleashing Natural IL18 Activity Using an Anti-IL18BP Blocker Induces Potent Immune Stimulation and Antitumor Effects
Menachem A, Alteber Z, Cojocaru G, Fridman Kfir T, Blat D, Leiderman O, Galperin M, Sever L, Cohen N, Cohen K, Granit RZ, Vols S, Frenkel M, Soffer L, Meyer K, Menachem K, Galon Tilleman H, Morein D, Borukhov I, Toporik A, Perpinial Shahor M, Tatirovsky E, Mizrachi A, Levy-Barda A, Sadot E, Strenov Y, Eitan R, Jakobson-Setton A, Yanichkin N, Ferre P, Ophir E
Cancer immunology research 2024
T cell dysfunction and therapeutic intervention in cancer.
Zebley CC, Zehn D, Gottschalk S, Chi H
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Strategies for Improving CAR T Cell Persistence in Solid Tumors
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Cancers 2024
The Multifaceted Roles of Hippo-YAP in Cardiovascular Diseases.
Wu H, Che YN, Lan Q, He YX, Liu P, Chen MT, Dong L, Liu MN
Cardiovascular toxicology 2024
IL-18R supported CAR T cells targeting oncofetal tenascin C for the immunotherapy of pediatric sarcoma and brain tumors.
Wickman E, Lange S, Wagner J, Ibanez J, Tian L, Lu M, Sheppard H, Chiang J, Koo SC, Vogel P, Langfitt D, Perry SS, Shanmugam R, Bell M, Shaw TI, Krenciute G, Zhang J, Gottschalk S
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Tao Z, Chyra Z, Kotulová J, Celichowski P, Mihályová J, Charvátová S, Hájek R
Blood Cancer Journal 2024
Preclinical studies show that Co-STARs combine the advantages of chimeric antigen and T cell receptors for the treatment of tumors with low antigen densities.
Mog BJ, Marcou N, DiNapoli SR, Pearlman AH, Nichakawade TD, Hwang MS, Douglass J, Hsiue EH, Glavaris S, Wright KM, Konig MF, Paul S, Wyhs N, Ge J, Miller MS, Azurmendi P, Watson E, Pardoll DM, Gabelli SB, Bettegowda C, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S
Science translational medicine 2024
CD47 expression is critical for CAR T-cell survival in vivo
Beckett AN, Chockley P, Pruett-Miller SM, Nguyen P, Vogel P, Sheppard H, Krenciute G, Gottschalk S, DeRenzo C
Journal for ImmunoTherapy of Cancer 2023
The role of FoxM1 in immune cells.
Zheng J, Bu X, Wei X, Ma X, Zhao P
Clinical and Experimental Medicine 2023
Synthetic biology-inspired cell engineering in diagnosis, treatment, and drug development
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Signal Transduction and Targeted Therapy 2023
Transcriptomic Approaches in Studies on and Applications of Chimeric Antigen Receptor T Cells
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Biomedicines 2023
Novel Fas-TNFR chimeras that prevent Fas ligand-mediated kill and signal synergistically to enhance CAR T cell efficacy
McKenzie C, El-Kholy M, Parekh F, Robson M, Lamb K, Allen C, Sillibourne J, Cordoba S, Thomas S, Pule M
2023
Enhancing CAR T-cell Therapy Using Fab-Based Constitutively Heterodimeric Cytokine Receptors
Righi M, Gannon I, Robson M, Srivastava S, Kokalaki E, Grothier T, Nannini F, Allen C, Bai YV, Sillibourne J, Cordoba S, Thomas S, Pule M
Cancer immunology research 2023
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Science Immunology 2023
A Costimulatory CAR Improves TCR-based Cancer Immunotherapy
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Cancer immunology research 2022
Revolution of CAR Engineering For Next-Generation Immunotherapy In Solid Tumors.
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Frontiers in immunology 2022
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Cells 2022
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Nature Biomedical Engineering 2022
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Nature 2022
speedingCARs: accelerating the engineering of CAR T cells by signaling domain shuffling and single-cell sequencing.
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