Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies
Open accessAbstract
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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PROTACs that target MAP4K1 (HPK1) have been described with promising preclinical activity.
“Most recently, PROTACs that target mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1; also known as HPK1) have been described with promising preclinical activity180”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [180]
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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
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2020-10
- Volume
- 38
- Issue
- 4
- Pages
- 551-566.e11
- ISSN
- 1535-6108 (ISSN-L)
- 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
- 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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