Cited by 214Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyCAR-T cell therapy research

The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.

Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies

Open access

Si, Jingwen, Shi, Xiangjun, Sun, Shuhao, Zou, Bin, Li, Yaopeng, An, Dongjie, Lin, Xingyu, Gao, Yan, Long, Fei, Pang, Bo, Liu, Xing, Liu, Tian, Chi, Wenna, Chen, Ligong, Dimitrov, Dimiter S., Sun, Yan, Du, Xinru, Yin, Wen, Gao, Guangxun, Min, Junxia, Wei, Lai, Liao, Xuebin·2020·Cancer Cell

DOI 10.1016/j.ccell.2020.08.001

Open this paper in CoChat — free account Open PDF

Abstract

Ameliorating T cell exhaustion and enhancing effector function are promising strategies for the improvement of immunotherapies. Here, we show that the HPK1-NFκB-Blimp1 axis mediates T cell dysfunction. High expression of MAP4K1 (which encodes HPK1) correlates with increased T cell exhaustion and with worse patient survival in several cancer types. In MAP4K1KO mice, tumors grow slower than in wild-type mice and infiltrating T cells are less exhausted and more active and proliferative. We further show that genetic depletion, pharmacological inhibition, or proteolysis targeting chimera (PROTAC)-mediated degradation of HPK1 improves the efficacy of CAR-T cell-based immunotherapies in diverse preclinical mouse models of hematological and solid tumors. These strategies are more effective than genetically depleting PD-1 in CAR-T cells. Thus, we demonstrate that HPK1 is a mediator of T cell dysfunction and an attractive druggable target to improve immune therapy responses.

Integrity signals

Registry

Crossref · 10.1016/j.ccell.2020.08.001

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Molecular and cellular insights into T cell exhaustion
Wherry, E. J., & Kurachi, M. (2015) · Nature Reviews Immunology · doi:10.1038/nri3862 · Cited by 4,652
A guide to cancer immunotherapy: from T cell basic science to clinical practice
Waldman, A. D., Fritz, J. M., & Lenardo, M. J. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0306-5 · Cited by 4,154
T cell exhaustion
Wherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062
Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S.-J., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.09.006 · Cited by 2,103
Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex rearrangements
Kosicki, M., Tomberg, K., & Bradley, A. (2018) · Nature Biotechnology · doi:10.1038/nbt.4192 · Cited by 1,883
Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection
Eyquem, J., Mansilla-Soto, J., Giavridis, T., van der Stegen, S. J. C., Hamieh, M., Cunanan, K. M., Odak, A., Gönen, M., & Sadelain, M. (2017) · Nature · doi:10.1038/nature21405 · Cited by 1,831
4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors
Long, A. H., Haso, W. M., Shern, J. F., Wanhainen, K. M., Murgai, M., Ingaramo, M., Smith, J. P., Walker, A. J., Kohler, M. E., Venkateshwara, V. R., et al. (2015) · Nature Medicine · doi:10.1038/nm.3838 · Cited by 1,815
Patient-Derived Xenograft Models: An Emerging Platform for Translational Cancer Research
Hidalgo, M. M., Amant, F. C., Biankin, A. V., Budínská, E., Byrne, A. T., Caldas, C., Clarke, R. B., de Jong, S., Jonkers, J., Mælandsmo, G. M., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0001 · Cited by 1,797
Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia
Fraietta, J. A., Lacey, S. F., Orlando, E. J., Pruteanu-Malinici, I., Gohil, M., Lundh, S., Boesteanu, A. C., Wang, Y., O’Connor, R. S., Hwang, W.-T., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0010-1 · Cited by 1,785
Defining ‘T cell exhaustion’
Blank, C. U., Haining, W. N., Held, W., Hogan, P. G., Kallies, A., Lugli, E., Lynn, R. C., Philip, M., Rao, A., Restifo, N. P., et al. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0221-9 · Cited by 1,603
Clonal replacement of tumor-specific T cells following PD-1 blockade
Yost, K. E., Satpathy, A. T., Wells, D. K., Qi, Y., Wang, C., Kageyama, R., McNamara, K. L., Granja, J. M., Sarin, K. Y., Brown, R. A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0522-3 · Cited by 1,534
Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.11.006 · Cited by 1,355
T Cell Dysfunction in Cancer
Thommen, D. S., & Schumacher, T. N. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.012 · Cited by 1,351
Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade
Pauken, K. E., Sammons, M. A., Odorizzi, P. M., Manne, S., Godec, J., Khan, O., Drake, A. M., Chen, Z., Sen, D. R., Kurachi, M., et al. (2016) · Science · doi:10.1126/science.aaf2807 · Cited by 1,348
The Principles of Engineering Immune Cells to Treat Cancer
Lim, W. A., & June, C. H. (2017) · Cell · doi:10.1016/j.cell.2017.01.016 · Cited by 1,103
Chromatin states define tumour-specific T cell dysfunction and reprogramming
Philip, M., Fairchild, L., Sun, L., Horste, E. L., Camara, S., Shakiba, M., Scott, A. C., Viale, A., Lauer, P., Merghoub, T., et al. (2017) · Nature · doi:10.1038/nature22367 · Cited by 933
CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells
Rupp, L. J., Schumann, K., Roybal, K. T., Gate, R. E., Ye, C. J., Lim, W. A., & Marson, A. (2017) · Scientific Reports · doi:10.1038/s41598-017-00462-8 · Cited by 757
MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade.
Ebert, P. J. R., Cheung, J., Yang, Y., McNamara, E., Hong, R., Moskalenko, M., Gould, S. E., Maecker, H., Irving, B. A., Kim, J. M., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.01.024 · Cited by 713
CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions
Hashimoto, M., Kamphorst, A. O., Im, S. J., Kissick, H. T., Pillai, R. N., Ramalingam, S. S., Araki, K., & Ahmed, R. (2018) · Annual Review of Medicine · doi:10.1146/annurev-med-012017-043208 · Cited by 674
Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN
Sievers, Q. L., Petzold, G., Bunker, R. D., Renneville, A., Słabicki, M., Liddicoat, B. J., Abdulrahman, W., Mikkelsen, T., Ebert, B. L., & Thomä, N. H. (2018) · Science · doi:10.1126/science.aat0572 · Cited by 537
Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF
Quigley, M. M., Pereyra, F., Nilsson, B., Porichis, F., Fonseca, C., Eichbaum, Q. G., Jülg, B. D., Jesneck, J. L., Brosnahan, K., Imam, S., et al. (2010) · Nature Medicine · doi:10.1038/nm.2232 · Cited by 527
Delineating the role of cooperativity in the design of potent PROTACs for BTK
Zorba, A., Nguyen, C., Xu, Y., Starr, J., Borzilleri, K., Smith, J., Zhu, H., Farley, K. A., Ding, W., Schiemer, J., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1803662115 · Cited by 419
Emerging Cellular Therapies for Cancer
Guedan, S., Ruella, M., & June, C. H. (2018) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041407 · Cited by 394
Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression
Zhou, B. N., Hu, J., Xu, F., Chen, Z., Bai, L., Fernández‐Salas, E., Lin, M., Liu, L., Yang, C., Zhao, Y., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01816 · Cited by 376
Multifunctional role of the transcription factor Blimp-1 in coordinating plasma cell differentiation
Minnich, M., Tagoh, H., Bönelt, P., Axelsson, E., Fischer, M., Cebolla, B., Tarakhovsky, A., Nutt, S. L., Jaritz, M., & Busslinger, M. (2016) · Nature Immunology · doi:10.1038/ni.3349 · Cited by 335
Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell–mediated immune responses
Shui, J., Boomer, J. S., Han, J., Xu, J. Q., Dement, G. A., Zhou, G., & Tan, T. (2006) · Nature Immunology · doi:10.1038/ni1416 · Cited by 234
BLIMP1 guides the fate of effector B and T cells
Nutt, S. L., Fairfax, K. A., & Kallies, A. (2007) · Nature reviews. Immunology · doi:10.1038/nri2204 · Cited by 139
EZH2 Represses the B Cell Transcriptional Program and Regulates Antibody-Secreting Cell Metabolism and Antibody Production
Guo, M., Price, M. J., Patterson, D. G., Barwick, B. G., Haines, R. R., Kania, A. K., Bradley, J., Randall, T. D., Boss, J. M., & Scharer, C. D. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1701470 · Cited by 139
Peripheral Administration of IL-13 Induces Anti-inflammatory Microglial/Macrophage Responses and Provides Neuroprotection in Ischemic Stroke
Kołosowska, N., Keuters, M. H., Wojciechowski, S., Keksa-Goldsteine, V., Laine, M. T., Malm, T., Goldsteins, G., Koıstınaho, J., & Dhungana, H. (2019) · Neurotherapeutics · doi:10.1007/s13311-019-00761-0 · Cited by 133
The Kinase Activity of Hematopoietic Progenitor Kinase 1 Is Essential for the Regulation of T Cell Function
Hernandez, S., Qing, J., Hong, R., Du, X., Park, S., Lee, H.-M., Xu, M., Oh, S. A., Navarro, A., Roose-Girma, M., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.09.012 · Cited by 130
Self-citation
Identifying Novel Protein‐Protein Interactions Using Co‐Immunoprecipitation and Mass Spectroscopy
Free, R. B., Hazelwood, L. A., & Sibley, D. R. (2009) · Current Protocols in Neuroscience · doi:10.1002/0471142301.ns0528s46 · Cited by 101
Down-regulation of BLIMP1α by the EBV oncogene, LMP-1, disrupts the plasma cell differentiation program and prevents viral replication in B cells: implications for the pathogenesis of EBV-associated B-cell lymphomas
Vrzalikova, K., Vockerodt, M., Leonard, S. M., Bell, A. I., Wei, W., Schrader, A., Wright, K. L., Kube, D., Rowe, M., Woodman, C. B. J., et al. (2011) · Blood · doi:10.1182/blood-2010-09-307710 · Cited by 97
Mass spectrometry‐based immuno‐precipitation proteomics – The user's guide
ten Have, S., Boulon, S., Ahmad, Y., & Lamond, A. I. (2011) · PROTEOMICS · doi:10.1002/pmic.201000548 · Cited by 93
Hematopoietic Progenitor Kinase 1 Is a Negative Regulator of Dendritic Cell Activation
Alzabin, S., Bhardwaj, N., Kiefer, F., Sawasdikosol, S., & Burakoff, S. J. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0802631 · Cited by 89
Hematopoietic progenitor kinase 1 is a critical component of prostaglandin E2-mediated suppression of the anti-tumor immune response
Alzabin, S., Pyarajan, S., Yee, H. T., Kiefer, F., Suzuki, A., Burakoff, S. J., & Sawasdikosol, S. (2009) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-009-0761-0 · Cited by 84
Tick-TOX, it’s time for T cell exhaustion
Mann, T. H., & Kaech, S. M. (2019) · Nature Immunology · doi:10.1038/s41590-019-0478-y · Cited by 70
Attenuation of T Cell Receptor Signaling by Serine Phosphorylation-mediated Lysine 30 Ubiquitination of SLP-76 Protein
Wang, X., Li, J.-P., Chiu, L.-L., Lan, J., Chen, D.-Y., Boomer, J. S., & Tan, T. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.371062 · Cited by 67
T Helper Lymphocytes Rescue CTL from Activation-Induced Cell Death
Kennedy, R. B., & Celis, E. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.5.2862 · Cited by 65
IL-2 signaling prevents T cell anergy by inhibiting the expression of anergy-inducing genes
Duré, M., & Macián, F. (2008) · Molecular Immunology · doi:10.1016/j.molimm.2008.09.029 · Cited by 65
A critical evaluation of the approaches to targeted protein degradation for drug discovery
Chopra, R., Sadok, A., & Collins, I. (2019) · Drug Discovery Today: Technologies · doi:10.1016/j.ddtec.2019.02.002 · Cited by 53
Unexpected CRISPR on-target effects
Lee, H., & Kim, J.-S. (2018) · Nature Biotechnology · doi:10.1038/nbt.4207 · Cited by 46
Chronic Activation of the Kinase IKKβ Impairs T Cell Function and Survival
Krishna, S., Xie, D., Gorentla, B. K., Shin, J., Gao, J., & Zhong, X. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1102429 · Cited by 43
Interleukin-13 interferes with activation-induced t-cell apoptosis by repressing p53 expression
Yang, L., Xu, L., Liu, Z., Yang, G., Geng, X., Mo, L., Liu, Z., Zheng, P., & Yang, P. (2015) · Cellular and Molecular Immunology · doi:10.1038/cmi.2015.50 · Cited by 21
Proteomic analysis of mTOR inhibition-mediated phosphorylation changes in ribosomal proteins and eukaryotic translation initiation factors
Jiang, X., Feng, S., Chen, Y., Feng, Y., & Deng, H. (2016) · Protein & Cell · doi:10.1007/s13238-016-0279-0 · Cited by 16
Proteomic analysis of mTOR inhibition- mediated phosphorylation changes in ribosomal proteins and eukaryotic translation initiation factors
Xu, Jiang, Shan, S., Feng, Yuling, Chen, C., Yun, Haiteng, & Deng (2016) · 蛋白质与细胞：英文版 · Cited by 5

Sorted by citations

PROTAC targeted protein degraders: the past is prologue
Békés, M., Langley, D. R., & Crews, C. M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00371-6 · Cited by 3,395
CAR immune cells: design principles, resistance and the next generation
Labanieh, L., & Mackall, C. L. (2023) · Nature · doi:10.1038/s41586-023-05707-3 · Cited by 695
Advancing targeted protein degradation for cancer therapy
Dale, B., Cheng, M., Park, K., Kanıskan, H. Ü., Xiong, Y., & Jin, J. J. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00365-x · Cited by 697
Proteolysis-targeting chimeras (PROTACs) in cancer therapy
Li, X., Pu, W., Zheng, Q., Ai, M., Chen, S., & Peng, Y. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01434-3 · Cited by 389
An overview of PROTACs: a promising drug discovery paradigm
Zi, L., Hu, M., Yu, Y., Du, C., Zhou, H., Liu, C., Chen, Y., Fan, L., Ma, H., Gong, Y., et al. (2022) · Molecular Biomedicine · doi:10.1186/s43556-022-00112-0 · Cited by 380

See all 214

Authors: Si, J., Shi, X., Sun, S., Zou, B., Li, Y., An, D., Lin, X., Gao, Y., Long, F., Pang, B., Liu, X., Liu, T., Chi, W., Chen, L., Dimitrov, D. S., Sun, Y., Du, X., Yin, W., Gao, G., Min, J., Wei, L., & Liao, X.
Affiliations: National Institute of Biological Sciences, Beijing (CN)
Tsinghua University (CN)
Sun Yat-sen University (CN)
Capital Medical University (CN)
China Academy of Chinese Medical Sciences (CN)
Central South University (CN)
University of Pittsburgh (US)
Lanzhou Institute of Husbandry and Pharmaceutical Sciences (CN)
Beijing Chao-Yang Hospital, Capital Medical University (CN)
Xijing Hospital (CN)
First Affiliated Hospital Zhejiang University (CN)
Corresponding author: Wei, Lai
Liao, Xuebin
ORCID: Si, Jingwen
Shi, Xiangjun
Sun, Shuhao
Zou, Bin
Li, Yaopeng
An, Dongjie
Lin, Xingyu
Gao, Yan
Long, Fei
Pang, Bo
Liu, Xing
Chi, Wenna
Chen, Ligong
Dimitrov, Dimiter S.
Sun, Yan
Du, Xinru
Gao, Guangxun
Min, Junxia
Wei, Lai
Liao, Xuebin
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2020-10
Volume: 38
Issue: 4
Pages: 551-566.e11
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccell.2020.08.001
OpenAlex: W3081763916
Semantic Scholar: 40ab8b396854539d254f72dff6f7a6a9b2af7c39
Cited by: 209
References: 45
Citations by year: 2026: 40 · 2025: 49 · 2024: 39 · 2023: 42 · 2022: 24 · 2021: 15
FWCI: 7.58
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 376 d)
Locations: Cancer Cell (publishedVersion)
PubMed (publishedVersion)
Funders: Tsinghua University (PCT/CN2019/083499)
Ministry of Science and Technology of the People's Republic of China (2015CB943201)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Health Sciences › Medicine › Oncology › CAR-T cell therapy research
Keywords: HPK1, MAP4K1, T cell exhaustion, T cell dysfunction, NF-κB, Blimp-1, CAR T-cell therapy, cancer immunotherapy, hematologic cancer, solid tumors, PD-1
MeSH terms: Animals, Humans, Immunotherapy, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, T-Lymphocytes, Mice, SCID, Mice, Inbred NOD, Protein Serine-Threonine Kinases, Mice, Knockout, Jurkat Cells, K562 Cells, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Kaplan-Meier Estimate

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks