HPK1 Dysregulation-Associated NK Cell Dysfunction and Defective Expansion Promotes Metastatic Melanoma Progression.

Autor: Choi WS; Department of Microbiology, Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea., Kwon HJ; Department of Microbiology, Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea., Yi E; Department of Microbiology, Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea., Lee H; Department of Microbiology, Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea., Kim JM; Department of Microbiology, Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea., Park HJ; Department of Microbiology, Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea., Choi EJ; Department of Dermatology, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea., Choi ME; Department of Dermatology, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea., Sung YH; Department of Cell and Genetic Engineering, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea., Won CH; Department of Dermatology, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea., Sung CO; Department of Pathology, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea., Kim HS; Department of Microbiology, Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Aug; Vol. 11 (29), pp. e2400920. Date of Electronic Publication: 2024 Jun 03.
DOI: 10.1002/advs.202400920
Abstrakt: Distant metastasis, the leading cause of cancer death, is efficiently kept in check by immune surveillance. Studies have uncovered peripheral natural killer (NK) cells as key antimetastatic effectors and their dysregulation during metastasis. However, the molecular mechanism governing NK cell dysfunction links to metastasis remains elusive. Herein, MAP4K1 encoding HPK1 is aberrantly overexpressed in dysfunctional NK cells in the periphery and the metastatic site. Conditional HPK1 overexpression in NK cells suffices to exacerbate melanoma lung metastasis but not primary tumor growth. Conversely, MAP4K1-deficient mice are resistant to metastasis and further protected by combined immune-checkpoint inhibitors. Mechanistically, HPK1 restrains NK cell cytotoxicity and expansion via activating receptors. Likewise, HPK1 limits human NK cell activation and associates with melanoma NK cell dysfunction couples to TGF-β1 and patient response to immune checkpoint therapy. Thus, HPK1 is an intracellular checkpoint controlling NK-target cell responses, which is dysregulated and hijacked by tumors during metastatic progression.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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