{
  "abstract": "Purpose:: Claudin 18.2 (CLDN18.2), a tight junction protein normally expressed in the gastric epithelium and rendered accessible during malignant transformation, has emerged as a key therapeutic target. Here, we seek to characterize the immune microenvironment of CLDN18.2-expressing gastric cancer and identify immune features associated with CLDN18.2 expression status.\n\nExperimental Design:: Tumor-immune features were profiled in 103 patients with HER2-neg/low advanced gastric cancer treated with first-line immune checkpoint inhibitor (ICI) using multiplex immunohistochemistry [7,423,483 cells across 2,315 regions of interest (ROI)]. The findings were validated in five published whole-transcriptome sequencing/microarray cohorts (1,521 samples), including the landmark CheckMate 649 phase III trial. Spatial immune architecture was assessed by cellular neighborhood analysis. Digital spatial profiling (DSP) was performed on 480 ROIs from a CLDN18.2-annotated tissue microarray (75 patients).\n\nResults:: CLDN18.2high tumors showed reproducible enrichment of humoral pathways, with higher CD20+ B-cell density and enrichment of B-cell/plasma-cell signatures. CLDN18.2 status alone was not associated with response or survival on first-line ICI therapy; in CLDN18.2low tumors, B-cell enrichment was associated with ICI benefit, unlike CLDN18.2high tumors. Spatial analyses indicated that CLDN18.2high tumors preferentially harbored tumor-infiltrating B cells, rather than tertiary lymphoid structure/lymphoid aggregate–like neighborhoods, and this tumor-compartment localization was associated with diminished ICI benefit. DSP confirmed that CD20+ B-cell enrichment was most pronounced within tumor regions, alongside compartment-specific activation of humoral and extrafollicular response programs and interferon-associated and remodeling signatures.\n\nConclusions:: CLDN18.2high gastric cancer exhibits a humoral-enriched microenvironment with increased tumor-infiltrating B cells and spatial immune organization associated with reduced ICI benefit. Spatial and humoral-state biomarkers may inform ongoing CLDN18.2-directed combination trials.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.",
    "Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.",
    "Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.",
    "Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.",
    "Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, South Korea.",
    "Cancer Science Institute of Singapore, Singapore, Singapore.",
    "Krantz Family Center for Cancer Research, Massachusetts General Brigham Cancer Institute, Boston, Massachusetts.",
    "Harvard Medical School, Boston, Massachusetts.",
    "Broad Institute of MIT and Harvard, Cambridge, Massachusetts.",
    "Biomedical Informatics and Data Science, Yale School of Medicine, New Haven, Connecticut.",
    "Department of Pathology, Yale University, New Haven, Connecticut.",
    "Department of Medicine, National University of Singapore, Singapore, Singapore.",
    "Department of Pathology, National University Hospital, Singapore, Singapore.",
    "Integrated Central Operations and Research Enablers, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.",
    "Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.",
    "Institute of Computational Life Sciences, Zürich University of Applied Sciences (ZHAW), Winterthur, Switzerland.",
    "Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.",
    "Digital Analytics Laboratory, ImmunoQs Pte. Ltd., Singapore, Singapore.",
    "Department of Surgery, National University Hospital, Singapore, Singapore.",
    "Division of Surgical Oncology, National University Cancer Institute, Singapore, Singapore.",
    "Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.",
    "Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.",
    "Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.",
    "Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.",
    "Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.",
    "The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.",
    "Department of Microbiology, Singapore General Hospital, Singapore, Singapore.",
    "Duke-NUS Medical School, Singapore, Singapore.",
    "NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.",
    "Department of Pathology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, the Netherlands.",
    "Pathology and Data Analytics, Leeds Institute of Medical Research at St. James, University of Leeds, Leeds, United Kingdom.",
    "Singapore Gastric Cancer Consortium, Singapore, Singapore.",
    "Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.",
    "Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.",
    "Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore.",
    "Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.",
    "Singhealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore, Singapore.",
    "Division of Medical Oncology, Department of Medicine, Yale School of Medicine, New Haven, Connecticut."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 45,
  "authors": [
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      "name": "Joseph J. Zhao",
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      "name": "Choong-kun Lee",
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      "name": "Allison S.Y. Chan",
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      "name": "Yichen Dai",
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      "name": "Lit-Hsin Loo",
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      "name": "Angie Lay Keng Tan",
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      "name": "Takeshi Hagihara",
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      "name": "Daryl K.A. Chia",
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      "name": "Kevin M.S. Sim",
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      "name": "Ming Teh",
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      "name": "Izuma Nakayama",
      "orcid": "0000-0003-4987-1934"
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      "name": "Jierui Xu",
      "orcid": "0000-0003-1146-3775"
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      "name": "Matthew Chau Hsien Ng",
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      "name": "Robert Walsh",
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      "name": "Anand D. Jeyasekharan",
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      "name": "Heike I. Grabsch",
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      "name": "Wei Peng Yong",
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      "name": "Ignacio Vazquez-Garcia",
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      "name": "Samuel J. Klempner",
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      "name": "Kohei Shitara",
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      "name": "Patrick Tan",
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      "name": "María Rodríguez Martínez",
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      "name": "Sun Young Rha",
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  "bibtex": "https://research.draconitic.com/paper/dwxyksf3babj3.bib",
  "cited_by": 0,
  "doi": "10.1158/1078-0432.ccr-26-1382",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13725331/",
  "id": "dwxyksf3babj3",
  "issns": [
    "1078-0432",
    "1557-3265"
  ],
  "landing_url": "https://doi.org/10.1158/1078-0432.ccr-26-1382",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Checkpoint Blockade"
    ],
    [
      "heading",
      "Gastrointestinal Cancers"
    ],
    [
      "heading",
      "Immunology"
    ],
    [
      "heading",
      "Immunotherapy"
    ],
    [
      "heading",
      "Novel Biomarkers and Precision Medicine"
    ],
    [
      "heading",
      "Stomach Cancer"
    ],
    [
      "heading",
      "Tumor Microenvironment"
    ],
    [
      "heading",
      "Tumor Resistance to Immune Response"
    ],
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7201842347",
  "pdf_url": null,
  "pmcid": "PMC13725331",
  "pmid": "42565557",
  "published": "2026-08-07",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/dwxyksf3babj3.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T12:23:45Z",
      "native_id": "PMC13725331",
      "source": "pmc",
      "url": "https://doi.org/10.1158/1078-0432.ccr-26-1382"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "heading:Immunology",
      "subfield": "immunology"
    }
  ],
  "title": "Spatial Organization of Tumor-Infiltrating B Cells Informs Immune Checkpoint Inhibitor Response in Claudin 18.2–Expressing Gastric Cancer",
  "title_text": "Spatial Organization of Tumor-Infiltrating B Cells Informs Immune Checkpoint Inhibitor Response in Claudin 18.2–Expressing Gastric Cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:21:37Z",
  "url": "https://research.draconitic.com/paper/dwxyksf3babj3",
  "venue": "Clinical Cancer Research",
  "versions": []
}