Spatial organisation of tumor-infiltrating B-cells informs immune checkpoint inhibitor response in Claudin 18.2-expressing gastric cancer

作者：Joseph J. Zhao, Choong‐kun Lee, Allison Chan, Steven M. Blum, Chang Li, Haoran Ma, Wenyi Luo, Supriya Srivastava, Huey Yew Jeffrey Lum, Norbert S. C. Tay, Woo Sun Kwon, Sejung Park, Craig Ryan Joseph, Li Yen Chong, Minkyu Jung, Shruti Sridhar, Aurélien Pélissier, Nilay Bhatt, Jia-Ying Joey Lee, Yichen Dai, Lit‐Hsin Loo, Angie Lay Keng Tan, Takeshi Hagihara, Felicia Wee, Daryl Kai Ann Chia, Kevin M. S. Sim, Ming Teh, Izuma Nakayama, Jierui Xu, Matthew Chau Hsien Ng, Robert Walsh, Joe Yeong, Anand D. Jeyasekharan, Heike I. Grabsch, Jimmy Bok Yan So, Wei Peng Yong, Ignacio Vázquez-Garćıa, Lloyd Bod, Samuel J. Klempner, Kohei Shitara, Yelena Y. Janjigian, Patrick Tan, María Rodríguez Martínez, Sun Young Rha, Raghav Sundar · 发表于：Clinical Cancer Research · 年份：2026 · DOI：10.1158/1078-0432.ccr-26-1382 · 研究领域：Barrier Structure and Function Studies、Ferroptosis and cancer prognosis、Immune cells in cancer

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 thi...