{
  "abstract": "Background Many patients with cancer benefit little from immune checkpoint blockade (ICB), a major obstacle to immunotherapy for decades. Finding alternative immune checkpoints that control CD8 + T-cell exhaustion is urgent if we are to improve the efficacy of immunotherapies, particularly in microsatellite stable (MSS) colorectal cancer (CRC) that is resistant to ICB.Methods Spatial proximity is essential for suppressive ligand-receptor signaling. Here, we mapped the spatial tumor microenvironment of patients with MSS CRC at single-cell resolution and analyzed the cells interacting with exhausted CD8 + T cells to identify immune checkpoint ligand-receptor pairs. To investigate the function of this previously unrecognized immune checkpoint, we performed validation studies spanning cellular experiments, mouse models, and clinical patient samples.Results We found that a subset of MSS CRC exhibits substantial CD8 + T-cell infiltration, but their function is suppressed. We identified CLEC2B (ligand)-KLRB1 (receptor) as a novel inhibiting ligand-receptor pair for CD8+ T cells. KLRB1 acts as an immune checkpoint receptor, increasing CD8+ T-cell exhaustion and facilitating immune escape in various human cancers. Binding of CLEC2B to KLRB1 initiates immunosuppressive signaling in CD8+ T cells. Clinically, CLEC2B-KLRB1 expression correlates positively with cancer progression and poor response to ICB, demonstrating that KLRB1+ CD8+ T cells are a key marker of the poorly responsive ICB subtype. Furthermore, blocking CLEC2B-KLRB1 signaling with antibodies enhances the antitumor function of CD8+ T cells, providing a potential immunotherapy target for ICB non-responders.Conclusions Our study revealed CLEC2B-KLRB1 as a previously unrecognized immune checkpoint axis that drives T-cell exhaustion specifically in ICB poor responsive MSS CRC. Blockade of KLRB1 with a therapeutic antibody reinvigorated CD8 + T-cell antitumor immunity, positioning this axis as a promising target for enhancing immunotherapy efficiency in malignancies, including CRC and other ICB-resistant cancers.",
  "authors": [
    {
      "affiliations": [
        "Department of Pathology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Institute of Pathology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China"
      ],
      "name": "Jie Cheng"
    },
    {
      "affiliations": [
        "Department of Pathology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Institute of Pathology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China"
      ],
      "name": "Jiahua Lu"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China",
        "Center for Precision Diagnosis and Treatment of Colorectal Cancer and Inflammatory Diseases, Peking University Health Science Center, Beijing, China"
      ],
      "name": "Zhaoya Gao"
    },
    {
      "affiliations": [
        "State Key Laboratory of Molecular Oncology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China"
      ],
      "name": "Yifeng Xiao"
    },
    {
      "affiliations": [
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Unit III of Gastrointestinal Cancer Centre, Peking University Cancer Hospital and Institute, Haidian District Beijing, China"
      ],
      "name": "Pengju Chen"
    },
    {
      "affiliations": [
        "Department of Pathology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, China",
        "Institute of Pathology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China"
      ],
      "name": "Mengting Zhou"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China",
        "Center for Precision Diagnosis and Treatment of Colorectal Cancer and Inflammatory Diseases, Peking University Health Science Center, Beijing, China"
      ],
      "name": "Dandan Huang"
    },
    {
      "affiliations": [
        "School of Life Sciences, Center for Statistical Science, Peking University, Beijing, China"
      ],
      "name": "Zihao Zhao"
    },
    {
      "affiliations": [
        "State Key Laboratory of Natural and Biomimetic Drugs, Beijing, China"
      ],
      "name": "Xiaohui Zhang"
    },
    {
      "affiliations": [
        "National \"111” Center for Cellular Regulation and Molecular Pharmaceutics (Ministry of Education), Hubei University of Technology, Wuhan, China"
      ],
      "name": "Yuan Zhao"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China",
        "Center for Precision Diagnosis and Treatment of Colorectal Cancer and Inflammatory Diseases, Peking University Health Science Center, Beijing, China"
      ],
      "name": "Ming Li"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China",
        "Center for Precision Diagnosis and Treatment of Colorectal Cancer and Inflammatory Diseases, Peking University Health Science Center, Beijing, China",
        "Peking University International Cancer Institute, Peking University, Beijing, China",
        "Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China",
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing, China"
      ],
      "name": "Jin Gu"
    }
  ],
  "title": "CLEC2B-KLRB1 axis acts as an immune checkpoint, governing the exhaustion of CD8+ T cells and their resistance to immune checkpoint blockade",
  "uid": "f1bcc6e6-8007-5719-9cbd-e2520dc970a0"
}