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 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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
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?
In the citing paper
“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]
Citations
Cites
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
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
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
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
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
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
Cited by
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
Metadata
- 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
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
