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Immune Cells in Cancer / Ferroptosis and Cancer Prognosis · Journal article
Clinical Cancer Research · August 7, 2026
Encouraging direction, but not yet definitive.
This prospective observational study identifies spatial organization of tumor-infiltrating B-cells as a biomarker associated with reduced benefit from first-line ICI in CLDN18.2-expressing gastric cancer, independent of CLDN18.2 status alone. The finding was validated across five published cohorts including a phase 3 trial. These results suggest spatial and humoral-state biomarkers may help stratify ICI response in this population, but prospective validation through biomarker-driven clinical trials is needed.
Prospective observational cohort with multi-cohort retrospective validation. 103 patients with HER2-negative/low advanced gastric cancer receiving first-line immune checkpoint inhibitor therapy. Intervention: First-line immune checkpoint inhibitor therapy. n = 103.
CLDN18.2high tumors showed enrichment of humoral pathways with higher CD20+ B-cell density and enriched B-cell/plasma-cell signatures In CLDN18.2low tumors, B-cell enrichment was associated with ICI benefit; in CLDN18.2high tumors, this association was absent CLDN18.2high tumors preferentially harbored tumor-infiltrating B-cells rather than tertiary lymphoid structure neighborhoods, which was associated with diminished ICI benefit
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These findings suggest that spatial B-cell localization (tumor-infiltrating versus lymphoid aggregate organization) may refine ICI response prediction in CLDN18.2-expressing gastric cancer beyond CLDN18.2 status alone. Clinicians should consider spatial immune profiling as a potential biomarker in ongoing CLDN18.2-directed combination trials, pending prospective validation.
Prospective profiling study identifying spatial B-cell organization as a potential biomarker for ICI response in CLDN18.2-expressing gastric cancer, with validation across five cohorts including a phase 3 trial, but lacking randomized comparison or prospective outcome prediction.
As stated by the source record.
Quoted from the source exactly as published.
These findings suggest that spatial B-cell localization (tumor-infiltrating versus lymphoid aggregate organization) may refine ICI response prediction in CLDN18.2-expressing gastric cancer beyond CLDN18.2 status alone. Clinicians should consider spatial immune profiling as a potential biomarker in ongoing CLDN18.2-directed combination trials, pending prospective validation.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
PURPOSE: Claudin 18.2 (CLDN18.2), a tight junction protein normally expressed in 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. PATIENTS AND METHODS: Tumor immune features were profiled in 103 patients with HER2-neg/low advanced GC treated with first-line immune checkpoint inhibitor (ICI) using multiplex immunohistochemistry (7,423,483 cells across 2,315 regions of interest [ROIs]). Findings were validated in five published whole-transcriptome sequencing/microarray cohorts (1,521 samples), including the CheckMate 649 phase 3 trial. Spatial 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). RESULTS: 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 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 extra-follicular response programs and interferon-associated and remodeling signatures. CONCLUSIONS: CLDN18.2high GC 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.
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