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

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

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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

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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.

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BindingDB Entry 50019270: Development of a series of quinazoline-2,5-diamine derivatives as potent hematopoietic progenitor kinase 1 (HPK1) inhibitors.
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BindingDB Entry 50018179: Discovery of Pyrazolopyridine Derivatives as HPK1 Inhibitors.
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BindingDB Entry 50023125: Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor.
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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

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

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