Sun and Xu et al. showed that high expression of the C-type lectin receptor CLEC12B by tumor-infiltrating cells correlated with poor clinical prognosis in patients with HCC. NK cell- specific-Clec12b-/- mice exhibited reduced cancer cell growth and extended survival in HCC, CRC, and metastatic melanoma models. CLEC12B was upregulated on NK cells in the TIME and interacted with lipoprotein lipase to induce CLEC12B–ITIM-mediated inhibitory signaling in NK cells. A nanobody specific for CLEC12B safely revived NK cell activity, suppressed tumor progression, and synergized with anti-PD-1 and chemotherapy in mouse and humanized mouse tumor models.
Contributed by Paula Hochman
ABSTRACT: Natural killer (NK) cells are innate immune effectors, but their cytotoxic potential can be compromised within the immunosuppressive tumor microenvironment. Identifying molecular mechanisms that underly this dysfunction is essential for advances in cancer immunotherapy. Here we show that CLEC12B, a C-type lectin receptor, functions as an inhibitory checkpoint that restricts NK cell-mediated antitumor immunity. High expression of CLEC12B by tumor-infiltrating NK cells correlates with poor clinical prognosis in patients with hepatocellular carcinoma. We identify lipoprotein lipase as a functional ligand for CLEC12B, triggering inhibitory signaling that suppresses NK cell activation. We developed a high-affinity nanobody as a potential therapeutic that disrupts the CLEC12B-lipoprotein lipase axis, thereby revitalizing NK cell activity and suppressing tumor progression in preclinical models. Furthermore, this nanobody has potent synergistic efficacy when combined with PD-1 blockade. These findings establish CLEC12B as a promising therapeutic target for rearming the immune system against solid malignancies.
Author Info: (1) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Prov
Author Info: (1) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (2) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (3) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (4) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (5) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (6) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (7) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (8) Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (9) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (10) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Transplant & Immunology Laboratory, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. The Transplantation Center, First Affiliated Hospital, School of Life Sciences and Medical Center, University of Sciences & Technology of China, Hefei, China. Research Centre of Big Data and Artificial Intelligence of Medicine, Hospital of Sun Yat-Sen University, Guangzhou, China. (11) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. charless@ustc.edu.cn. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. charless@ustc.edu.cn.
