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c-Jun overexpression in CAR T cells induces exhaustion resistance
Open accessAbstract
Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer 1-3, but dysfunction due to T cell exhaustion is an important barrier to progress 4-6. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system with a tonically signaling CAR, which induces hallmark features of exhaustion 6. Exhaustion was associated with a profound defect in the production of IL-2, along with increased chromatin accessibility of AP-1 transcription factor motifs and overexpression of the bZIP and IRF transcription factors that have been implicated in mediating dysfunction in exhausted T cells 7-10. Here we show that CAR T cells engineered to overexpress the canonical AP-1 factor c-Jun have enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved anti-tumour potency in five different mouse tumour models in vivo. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells, and that engineering CAR T cells to overexpress c-Jun renders them resistant to exhaustion, thereby addressing a major barrier to progress for this emerging class of therapeutic agents.
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“T cell exhaustion also limits the efficacy of chimeric antigen receptor (CAR) T cell therapy against solid tumours14–17.”
From Proteotoxic stress response drives T cell exhaustion and immune evasion (2025) · cites this paper as [14]
In the citing paper
“Next-generation T cell therapies are being engineered with transgenes designed to overcome suppressive signals in the tumor environment (Kloss et al., 2018; Lynn et al., 2019; Yamamoto et al., 2019).”
From Pooled Knockin Targeting for Genome Engineering of Cellular Immunotherapies (2020) · cites this paper as Lynn et al., 2019
In the citing paper
“c-Jun overexpression protects CAR-T cells from dysfunction by inducing T-cell exhaustion resistance [157].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [157]
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“Transcription factors are able to exert large phenotypic changes and guide T-cell 13 differentiation (10) making them an appealing target in TCR/CAR T-cell 14 immunotherapy.”
BackgroundMassively parallel knock-in engineering of human T cells
Dai, X., Park, J. J.-Y., Du, Y., Na, Z., Lam, S. Z., Chow, R. D.-W., Renauer, P. A., Gu, J., Shan, X., Chu, Z., et al. (2023) · Nature Biotechnology · doi:10.1038/s41587-022-01639-x · Cited by 56
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“c-Jun OE showed enhanced expansion potential, cytotoxicity and diminished terminal exhaustion differentiation; Leukemia (Nalm6-GD2); Osteosarcoma (143B) M / (12)”
BackgroundInfluentialGenome-wide CRISPR screens identify critical targets to enhance CAR-NK cell antitumor potency
Biederstädt, A., Başar, R., Park, J.-M., Uprety, N., Shrestha, R., Silva, F. R., Dede, M., Watts, J., Acharya, S., Xiong, D., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.07.021 · Cited by 56
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Breaking Bottlenecks for the TCR Therapy of Cancer
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“Genetic engineering to overexpress c-Jun, a protein that combines with c-Fos to form the transcription factor AP-1, can also increase expansion and prolong survival of adoptively transferred T cells after reinfusion by driving transcription of IL-2 [114].”
BackgroundInfluentialRegulatory T-cell therapy approaches
McCallion, O., Bilici, M., Hester, J., & Issa, F. (2022) · Clinical & Experimental Immunology · doi:10.1093/cei/uxac078 · Cited by 52
“Similarly, overexpression of c-Jun (a downstream JNK target) in CAR-T cells renders them resistant to exhaustion, likely mediated through disruption of AP-1-driven expression of exhaustion-associated gene networks [96].”
BackgroundWartewig, T., Daniels, J., Schulz, M., Hameister, E., Joshi, A., Park, J., Morrish, E., Venkatasubramani, A. V., Cernilogar, F. M., van Heijster, F. H. A., et al. (2023) · Nature Cancer · doi:10.1038/s43018-023-00635-7 · Cited by 54
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BackgroundMizukoshi, E., Nakagawa, H., Tamai, T., Kitahara, M., Fushimi, K., Nio, K., Terashima, T., Iida, N., Arai, K., Yamashita, T., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30861-z · Cited by 50
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“C-Jun is an important member of the AP-1 proteins, forming homodimers with Jun family members or heterodimers with Fos family, which has been well documented to be highly expressed in various tumors, including breast cancer, lung cancer and melanoma [6–8].”
Innate and adaptive immune escape mechanisms of hepatitis B virus
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“88 An interesting study conducted by Mackall and her colleagues involving two cohorts of patients with large B cell lymphoma treated with axi-cel evaluated the association between the phenotypic profile of CAR-T cells infused in these patients and the clinical progression of the disease.”
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“Published ChIP-seq data of JUN, BATF, and IRF4 were downloaded from the Gene Expression Omnibus database [3, 28].”
BackgroundMethodResultInfluentialThe clinical landscape of CAR-engineered unconventional T cells
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“6,22 Consequently, MEKIs facilitated the proliferation and killing potential of bulk GD2 CAR-T cells (Supplementary Figs.”
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“Other approaches include overexpression of genomic targets that increase persistence and limit exhaustion, such as FOXO1 or c-Jun ( JUN ), or deleting genes such as PTPN2 , which is associated with T cell exhaustion 71–73 .”
Early programming of CD8 + T cell response by the orphan nuclear receptor NR4A3
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“This interpretation is supported by a recent report demonstrating that CAR T cells overexpressing c-Jun are more functional and undergo less terminal differentiation (42).”
ResultBidirectional epigenetic editing reveals hierarchies in gene regulation
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“8h), indicating a reduced capacity for IL2 production in HA-GD2-28z-CAR T cells, as expected in T cell exhaustion 81,82 .”
Self-citationIn vivo CRISPR screens identify modifiers of CAR T cell function in myeloma
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“In addition, continuous expression of c-Jun in T cells enhanced CAR-T cell function (Lynn et al., 2019).”
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“Conversely, overexpression of the canonical AP-1 factor c-Jun has been shown to induce exhaustion resistance of antitumor CAR-T cells (56).”
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“Other proposed CRISPR targets attracting attention by biotech and pharmaceutical companies are PTPN2, NR4A and c-JUN (126, 127, 131).”
Backgroundvan de Sandt, C. E., Nguyen, T. H. O., Gherardin, N. A., Crawford, J. C., Samir, J., Minervina, A. A., Pogorelyy, M. V., Rizzetto, S., Szeto, C. W., Kaur, J., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01633-8 · Cited by 47
“39), KLF2 , SELL , TXNIP , PIK3IP1 , CD37 and TRBV27 , displayed less-differentiated cell states, lacked exhaustion genes, expressed AP-1 transcription factors FOS and JUN (progenitor of exhaustion in acute infection 53 ), C-JUN (resistance to exhaustion 43 ) and distinct clonal lineages.”
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“Some examples include the overexpression of the AP-1 family member c-Jun and the deletion of molecules such as the methyltransferase DNMT3A, the in fl ammatory regulators REGNASE-1 and ROQUIN-1, and the transcription factors PRDM1and NR4A3 11,25,27,28 .”
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“If not stated elsewhere, on days 10 – 11 following initialTcellactivation using CD3/CD28 Tcellactivator, we used CAR T cells in vitro experiments or implanted them into mouse models 49 .”
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“conditioning, even at the low levels, has been demonstrated to initiate and enhance development of exhaustion [61].”
BackgroundHuang, S., Jiao, X., Lu, D., Pei, X., Qi, D., & Li, Z. (2021) · The Ocular Surface · doi:10.1016/j.jtos.2021.02.001 · Cited by 41
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“Hence, various strategies to increase CAR T longevity are explored (Eyquem et al., 2017; Lynn et al., 2019).”
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“Research has displayed that exhausted CD8+ T cells from cancer patients express high levels of three NR4A transcription factors, which are initiated by NFAT [169,170].”
BackgroundStructural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens
Hwang, M. S., Miller, M. S., Thirawatananond, P., Douglass, J., Wright, K. M., Hsiue, E. H.-C., Mog, B. J., Aytenfisu, T. Y., Murphy, M. B., Azurmendi, P. A., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25605-4 · Cited by 38
Krüppel-like factor 4 regulates the cytolytic effector function of exhausted CD8 T cells
Nah, J., & Seong, R. H. (2022) · Science Advances · doi:10.1126/sciadv.adc9346 · Cited by 40
“Several studies have shown that CD8 T cells from tumor environment can be reinvigorated by immune checkpoint blockades, gene manipulations, and exogenous cytokine treatments (27, 44, 53, 60, 61).”
BackgroundResultLv, J., Qin, L., Zhao, R., Wu, D., Wu, Z., Zheng, D., Li, S., Luo, M., Wu, Q., Long, Y., et al. (2022) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2022.12.003 · Cited by 38
“High-affinity GD2-targeted CAR, composed of the anti-GD2 14g2a-E101K scFv, CD3z, and CD28 signaling domains, has been reported to cause CAR-T cell exhaustion by clustering on the T cell surface to trigger CAR signaling in the absence of antigen.(47) We knocked out CISH in the GD2-targeted CAR-T cells and found that GD…”
BackgroundSmirnov, S., Mateikovich, P., Samochernykh, K. A., & Shlyakhto, E. V. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1335424 · Cited by 42
“Another work devoted to the investigation of exhausted CAR-T cells the with CD28 signaling domain, found the increased expression of AP-1/bZIP and bZIP/ IRF transcription factors that have been implicated in regulation of exhaustion-related genes (87).”
BackgroundZhang, D. K. Y., Brockman, J. M., Adu‐Berchie, K., Liu, Y., Binenbaum, Y., de Lázaro, I., Sobral, M. C., Tresa, R., & Mooney, D. J. (2024) · Nature Biomedical Engineering · doi:10.1038/s41551-024-01216-4 · Cited by 41
“Various genetic tools are being used to develop next-generation therapies to improve antigen recognition and signalling 3–5 , maintain T-cell stemness 6,7 and minimize T-cell exhaustion 8 .”
Borcherding, N. C., Kim, W., Quinn, M. A., Han, F., Zhou, J. Q., Sturtz, A. J., Schmitz, A. J., Lei, T., Schattgen, S., Klebert, M. K., et al. (2024) · Nature Immunology · doi:10.1038/s41590-024-01888-9 · Cited by 36
Louie, R. H. Y., Cai, C., Samir, J., Singh, M., Deveson, I. W., Ferguson, J. M., Amos, T. G., McGuire, H. M., Gowrishankar, K., Adikari, T. N., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-43656-7 · Cited by 38
“Both clusters C2 and C3 contained a subset of cellsexpressing AP-1 transcription factors,e.g., FOS and JUN , whichare known to be associated with resistance to exhaustion in CAR T cells 34 , and a lack of these factors has been found to be indicative of progenitor of exhausted T cells 35 .”
Dimitri, A. J., Baxter, A. E., Chen, G. M., Hopkins, C. R., Rouin, G. T., Huang, H., Kong, W., Holliday, C., Wiebking, V., Bartoszek, R. L., et al. (2024) · Science Advances · doi:10.1126/sciadv.adp9371 · Cited by 42
“Strategies including genetic modification of CAR T cells to avert exhaustion ( 3 – 6 ) or use of immunotherapies such as programmed cell death protein 1 (PD1) blockade to reinvigorate T EX have been proposed to enhance treatment efficacy ( 7 ).”
Self-citationXu, X., Chen, H., Ren, Z., Xu, X., Wu, W., Yang, H., Wang, J., Zhang, Y., Zhou, Q., Li, H., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.11.005 · Cited by 44
Ponterio, E., Maria, R. D., & Haas, T. L. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.565631 · Cited by 37
Single cell multiomic analysis of T cell exhaustion in vitro
Corselli, M., Saksena, S., Nakamoto, M. A., Lomas, W. E., Taylor, I., & Chattopadhyay, P. K. (2021) · Cytometry Part A · doi:10.1002/cyto.a.24496 · Cited by 36
Mause, E. R. V., Baker, J. M., Dietze, K. A., Radhakrishnan, S. V., Iraguha, T., Omili, D. O., Davis, P. M., Chidester, S. L., Modzelewska, K., Panse, J., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.add7900 · Cited by 37
“As a result, the persistent signaling leads to the rapid depletion of c-Jun, a component of the T cell–activating AP-1 transcription factor (29).”
BackgroundInfluentialFunction and evolution of the prototypic CD28ζ and 4-1BBζ chimeric antigen receptors
Feucht, J., & Sadelain, M. (2020) · Immuno-Oncology Technology · doi:10.1016/j.iotech.2020.09.001 · Cited by 42
“Transcriptional and epigenetic alterations associated with T-cell exhaustion include epigenomic dysregulation of AP-1 transcription factor binding motifs and increased expression of the bZIP and IRF transcription factors, which have been implicated in mediating T-cell dysfunction.(55) Overexpression of the activating…”
BackgroundInfluentialFactors associated with long-term outcomes of CD19 CAR T-cell therapy for relapsed/refractory CLL
Liang, E. C., Albittar, A. A., Huang, J. J., Hirayama, A. V. V., Kimble, E. L., Portuguese, A. J., Chapuis, A. G., Shadman, M. S., Till, B. G., Cassaday, R. D., et al. (2023) · Blood Advances · doi:10.1182/bloodadvances.2023011399 · Cited by 38
Urolithin A Hijacks ERK1/2‐ULK1 Cascade to Improve CD8+ T Cell Fitness for Antitumor Immunity
Ma, S., Wu, Q., Wu, W., Tian, Y., Zhang, J., Chen, C., Sheng, X., Zhao, F., Ding, L., Wang, T., et al. (2024) · Advanced Science · doi:10.1002/advs.202310065 · Cited by 40
BATF is a major driver of NK cell epigenetic reprogramming and dysfunction in AML
Kumar, B., Singh, A. K., Başar, R., Uprety, N., Li, Y., Fan, H., Cortes, A. K. N., Kaplan, M., Acharya, S., Shaim, H., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adp0004 · Cited by 38
“…NK cells exhibited enrichment of motifs associated with CAR T/T cell exhaustion (BATF, BATF3, and interferon regulatory factor 4) ( 19 , 39 , 40 ), T cell dysfunction [DNA damage-inducible transcript 3 (DDIT3)] ( 41 ), and TGF-β /SMAD signaling (ELF3) ( 42 ), whereas…”
BackgroundQin, H., Zhou, Z., Shi, R., Mai, Y., Xu, Y., Fu, P., Cheng, G., Zhang, Z., Chen, W., Chen, Y., et al. (2025) · Journal of Hematology & Oncology · doi:10.1186/s13045-025-01701-6 · Cited by 43
Exploiting T cell signaling to optimize engineered T cell therapies
Wang, H., Song, X., Shen, L., Wang, X., & Xu, C. (2021) · Trends in cancer · doi:10.1016/j.trecan.2021.10.007 · Cited by 37
T Cell Engaging Immunotherapies, Highlighting Chimeric Antigen Receptor (CAR) T Cell Therapy
Bousser, E. D., Callewaert, N., & Festjens, N. (2021) · Cancers · doi:10.3390/cancers13236067 · Cited by 39
Resistance against anti-CD19 and anti-BCMA CAR T cells: Recent advances and coping strategies
Atilla, P. A., & Atilla, E. (2022) · Translational Oncology · doi:10.1016/j.tranon.2022.101459 · Cited by 37
Regulatory effects of IRF4 on immune cells in the tumor microenvironment
Lu, J., Liang, T., Li, P., & Yin, Q. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1086803 · Cited by 36
“(89) found that ectopic overexpression of cJun in exhausted CAR-T cells can effectively rescue exhaustion and restore anti-tumor activity by disrupting and/or displacing immunosuppressive transcriptional complexes containing IRF4 and AP1 family members (89).”
BackgroundInfluentialJung, I.-Y., Bartoszek, R. L., Rech, A. J., Collins, S. M., Ooi, S., Williams, E. F., Hopkins, C. R., Narayan, V., Haas, N. B., Frey, N. V., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-1175 · Cited by 35
Fine-tuning the antigen sensitivity of CAR T cells: emerging strategies and current challenges
Harrer, D. C., Li, S., Kaljanac, M., Barden, M., Pan, H., & Abken, H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1321596 · Cited by 34
Unlocking the potential of engineered immune cell therapy for solid tumors
Albarrán, V., Angelats, L., Delgado, J., Gros, A., Urbano-Ispizúa, Á., Guedan, S., & Prat, A. (2025) · Nature Communications · doi:10.1038/s41467-025-56527-0 · Cited by 39
Qin, Y., Huo, F., Feng, Z., Hou, J., Ding, Y., Wang, Q., Gui, Y., Yang, Z., Yang, J., Zhou, G., et al. (2025) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2024.0948 · Cited by 35
Lamure, S., Laethem, F. V., de Verbizier, D., Lozano, C., Gehlkopf, E., Tudesq, J., Serrand, C., Benzaoui, M., Kanouni, T., Quintard, A., et al. (2021) · Cancers · doi:10.3390/cancers13174279 · Cited by 38
“described distinct results on the ZUMA-1 cohort; flow cytometry analyses revealed that high percentages of naive-like (CCR7+CD45RA+) T-cells and a lower ex vivo doubling time was associated with a higher response rate [19,35,36].”
ResultIn vivo gene immunotherapy for cancer
Mai, D., June, C. H., & Sheppard, N. C. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abo3603 · Cited by 35
“The overexpression of c-Jun, an AP-1 factor, was found to enhance the functional capacity of CAR-T cells in several tumor mouse models and is the foundation of a platform technology that Lyell Immunopharma has applied to its T cell therapy candidates (49).”
BackgroundTargeting the epigenome to reinvigorate T cells for cancer immunotherapy
Xiong, D., Zhang, L., & Sun, Z. (2023) · Military Medical Research · doi:10.1186/s40779-023-00496-2 · Cited by 36
“…repeats (CRISPR)-associated protein 9 (CRISPR-Cas9) genome editing has facilitated direct modifications to the T cell epigenome, enabling the deletion of epigenetic regulators like TET2 or the insertion of TFs such as c-Jun and basic leucine zipper ATF-Like transcription factor (BATF) [217–219].”
BackgroundCAR‐T‐cell products in solid tumors: Progress, challenges, and strategies
Qian, K., Li, G., Zhang, S., Fu, W., Li, T., Zhao, J., Lei, C., Wang, Y., & Hu, S. (2024) · Interdisciplinary medicine · doi:10.1002/inmd.20230047 · Cited by 36
Yang, Y., Vedvyas, Y., Alcaina, Y., Trumper, S. J., Babu, D. S., Min, I. M., Tremblay, J. M., Shoemaker, C. B., & Jin, M. M. (2024) · JCI Insight · doi:10.1172/jci.insight.186268 · Cited by 37
“Additional engineering strategies might be considered to potentially augment CAR T cell activity without compromising selectivity, which include coexpressing transcriptional factors like c-Jun and FOXO1 (38, 39) or locally delivering inflammatory cytokines such as IL-12 (14).”
Xiang, B., Zhang, M., Li, K., Zhang, Z., Liu, Y., Gao, M., Wang, X., Xiao, X., Sun, Y., He, C. H., et al. (2025) · Nature Immunology · doi:10.1038/s41590-024-02047-w · Cited by 34
Wang, X., Zha, H., Wu, W., Yuan, T., Xie, S., Jin, Z., Long, H., Yang, F., Wang, Z., Zhang, A., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.abn5029 · Cited by 34
Metabolic reprogramming of CAR T cells: a new frontier in cancer immunotherapy
Frlic, T., & Pavlin, M. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1688995 · Cited by 38
“Forming activating NFAT-AP-1 complexes is vital for preventing T cell exhaustion, enhancing their long-term ability to proliferate, and supporting effective anti-tumor responses (200).”
Mechanisms of response and resistance to CAR T cell therapies
Berger, T. R., & Maus, M. V. (2021) · Current Opinion in Immunology · doi:10.1016/j.coi.2021.02.010 · Cited by 34
Anti-CAIX BBζ CAR4/8 T cells exhibit superior efficacy in a ccRCC mouse model
Wang, Y., Buck, A., Grimaud, M., Culhane, A. C., Kodangattil, S. R., Razimbaud, C., Bonal, D. M., Nguyen, Q., Zhu, Z., Wei, K. S., et al. (2021) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2021.12.019 · Cited by 34
Cai, C., Samir, J., Pirozyan, M. R., Adikari, T. N., Gupta, M., Leung, P., Hughes, B., Byl, W. V. D., Rizzetto, S., Elthala, A., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-35281-7 · Cited by 36
Analysis of causes for poor persistence of CAR-T cell therapy in vivo
Kong, Y., Tang, L. Y., You, Y., Li, Q., & Zhu, X. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1063454 · Cited by 36
“Therefore, CAR-T cells overexpressing c-Jun show enhanced expansion potential, reduced terminal differentiation, and improved antitumor efficacy (57).”
Background
Metadata
- Authors
- Lynn, R. C., Weber, E. W., Sotillo, E., Gennert, D., Xu, P., Good, Z., Anbunathan, H., Lattin, J., Jones, R., Tieu, V., Nagaraja, S., Granja, J., de Bourcy, C. F. A., Majzner, R., Satpathy, A. T., Quake, S. R., Monje, M., Chang, H. Y., & Mackall, C. L.
- Affiliations
- Lyell Immunopharma (United States) (US)
- Stanford Medicine (US)
- Stanford University (US)
- Parker Institute for Cancer Immunotherapy (US)
- Chan Zuckerberg Biohub San Francisco (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Mackall, Crystal L.
- ORCID
- Venue
- Nature
- Published
- 2019-12-04
- Volume
- 576
- Issue
- 7786
- Pages
- 293-300
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6944329
- OpenAlex
- W2992738455
- Cited by
- 891
- References
- 63
- Citations by year
- 2026: 141 · 2025: 151 · 2024: 138 · 2023: 129 · 2022: 122 · 2021: 119 · 2020: 89 · 2019: 1
- FWCI
- 34.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1s10od018220-01)
- National Human Genome Research Institute (RM1HG007735, P50HG007735)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- c-Jun, chimeric antigen receptor T cells, T cell exhaustion, AP-1 transcription factor, IL-2 deficiency, chromatin accessibility, IRF transcription factors, bZIP transcription factors, T cell expansion, antitumor immunity, CAR-T cell engineering
- MeSH terms
- Animals, Gene Expression Regulation, Humans, Neoplasms, Receptors, Antigen, T-Cell, Transcription, Genetic, Proto-Oncogene Proteins c-jun, Transcription Factor AP-1, Epigenesis, Genetic, Cell Line, Tumor, Mice
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