최우선 (울산대학교 의과대학) | 한빛사논문 > 한빛사

한빛사논문

조회344

최우선Woo Seon Choi

울산대학교 의과대학

Adv. Sci., 2024 Jun 3:e2400920 | https://doi.org/10.1002/advs.202400920 HPK1 Dysregulation-Associated NK Cell Dysfunction and Defective Expansion Promotes Metastatic Melanoma Progression

Woo Seon Choi ¹ ^†, Hyung-Joon Kwon ¹^†, Eunbi Yi ¹, Haeun Lee ¹, Jung Min Kim ¹, Hyo Jin Park ¹, Eun Ji Choi ², Myoung Eun Choi ², Young Hoon Sung ³, Chong Hyun Won ², Chang Ohk Sung ⁴^†^*, Hun Sik Kim ¹^†^*

¹Department of Microbiology, Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.

²Department of Dermatology, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.

³Department of Cell and Genetic Engineering, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.

⁴Department of Pathology, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.

^†W.S.C., H.-J.K., C.O.S., and H.S.K. contributed equally to this work.
^*Corresponding authors: correspondence to Chang Ohk Sung or Hun Sik Kim

Abstract

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.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-04)
연구진국내 연구진
분야 의약학 > 면역의학

댓글 작성 로그인

CV 열람하기

연락처 보기