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Peer-reviewedCC BY-NC-ND 4.0Clinical Cancer Research

Spatial Organization of Tumor-Infiltrating B Cells Informs Immune Checkpoint Inhibitor Response in Claudin 18.2–Expressing Gastric Cancer

  • Joseph J. Zhao1,2,3
  • Choong-kun Lee4,5
  • Allison S.Y. Chan6
  • Steven Blum7,8,9
  • Chang Li10
  • Haoran Ma3
  • Wenyi Luo11
  • Supriya Srivastava12
  • Huey Yew Jeffrey Lum13
  • Sheng Cong Norbert Tay6
  • Woo Sun Kwon5
  • Sejung Park5
33 more authors
  • Craig Ryan Joseph14
  • Li Yen Chong15
  • Minkyu Jung4,5
  • Shruti Sridhar6
  • Aurelien Pelissier10,16
  • Nilay Bhatt10
  • Jia-Ying Joey Lee17,18
  • Yichen Dai18
  • Lit-Hsin Loo17,18
  • Angie Lay Keng Tan3
  • Takeshi Hagihara3
  • Felicia Wee15
  • Daryl K.A. Chia19,20
  • Kevin M.S. Sim13
  • Ming Teh13
  • Izuma Nakayama21
  • Jierui Xu22
  • Matthew Chau Hsien Ng23
  • Robert Walsh24
  • Joe Poh Sheng Yeong15,25,26,27,28
  • Anand D. Jeyasekharan2,6,24,29
  • Heike I. Grabsch30,31
  • Jimmy Bok-Yan So2,19,20,32
  • Wei Peng Yong24,32
  • Ignacio Vazquez-Garcia7,8,9,33
  • Lloyd Bod7,8,9
  • Samuel J. Klempner8,9,34
  • Kohei Shitara21
  • Yelena Janjigian22
  • Patrick Tan3,28,32,35,36,37
  • María Rodríguez Martínez10
  • Sun Young Rha4,5
  • Raghav Sundar38
38 affiliations
  1. 1Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
  2. 2Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  3. 3Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
  4. 4Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
  5. 5Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, South Korea.
  6. 6Cancer Science Institute of Singapore, Singapore, Singapore.
  7. 7Krantz Family Center for Cancer Research, Massachusetts General Brigham Cancer Institute, Boston, Massachusetts.
  8. 8Harvard Medical School, Boston, Massachusetts.
  9. 9Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  10. 10Biomedical Informatics and Data Science, Yale School of Medicine, New Haven, Connecticut.
  11. 11Department of Pathology, Yale University, New Haven, Connecticut.
  12. 12Department of Medicine, National University of Singapore, Singapore, Singapore.
  13. 13Department of Pathology, National University Hospital, Singapore, Singapore.
  14. 14Integrated Central Operations and Research Enablers, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  15. 15Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  16. 16Institute of Computational Life Sciences, Zürich University of Applied Sciences (ZHAW), Winterthur, Switzerland.
  17. 17Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  18. 18Digital Analytics Laboratory, ImmunoQs Pte. Ltd., Singapore, Singapore.
  19. 19Department of Surgery, National University Hospital, Singapore, Singapore.
  20. 20Division of Surgical Oncology, National University Cancer Institute, Singapore, Singapore.
  21. 21Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
  22. 22Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
  23. 23Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
  24. 24Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
  25. 25Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.
  26. 26The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  27. 27Department of Microbiology, Singapore General Hospital, Singapore, Singapore.
  28. 28Duke-NUS Medical School, Singapore, Singapore.
  29. 29NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  30. 30Department of Pathology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, the Netherlands.
  31. 31Pathology and Data Analytics, Leeds Institute of Medical Research at St. James, University of Leeds, Leeds, United Kingdom.
  32. 32Singapore Gastric Cancer Consortium, Singapore, Singapore.
  33. 33Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
  34. 34Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
  35. 35Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore.
  36. 36Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  37. 37Singhealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore, Singapore.
  38. 38Division of Medical Oncology, Department of Medicine, Yale School of Medicine, New Haven, Connecticut.
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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.

Experimental 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).

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 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.

Conclusions:: 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.

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Cite

BibTeXRIS
BibTeX
@article{zhao2026spatial,
  title = {{Spatial Organization of Tumor-Infiltrating B Cells Informs Immune Checkpoint Inhibitor Response in Claudin 18.2–Expressing Gastric Cancer}},
  author = {Joseph J. Zhao and Choong-kun Lee and Allison S.Y. Chan and Steven Blum and Chang Li and Haoran Ma and Wenyi Luo and Supriya Srivastava and Huey Yew Jeffrey Lum and Sheng Cong Norbert Tay and Woo Sun Kwon and Sejung Park and Craig Ryan Joseph and Li Yen Chong and Minkyu Jung and Shruti Sridhar and Aurelien Pelissier and Nilay Bhatt and Jia-Ying Joey Lee and Yichen Dai and Lit-Hsin Loo and Angie Lay Keng Tan and Takeshi Hagihara and Felicia Wee and Daryl K.A. Chia and Kevin M.S. Sim and Ming Teh and Izuma Nakayama and Jierui Xu and Matthew Chau Hsien Ng and Robert Walsh and Joe Poh Sheng Yeong and Anand D. Jeyasekharan and Heike I. Grabsch and Jimmy Bok-Yan So and Wei Peng Yong and Ignacio Vazquez-Garcia and Lloyd Bod and Samuel J. Klempner and Kohei Shitara and Yelena Janjigian and Patrick Tan and María Rodríguez Martínez and Sun Young Rha and Raghav Sundar},
  journal = {Clinical Cancer Research},
  year = {2026},
  month = aug,
  doi = {10.1158/1078-0432.ccr-26-1382},
  url = {https://doi.org/10.1158/1078-0432.ccr-26-1382},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Spatial Organization of Tumor-Infiltrating B Cells Informs Immune Checkpoint Inhibitor Response in Claudin 18.2–Expressing Gastric Cancer
AU  - Joseph J. Zhao
AU  - Choong-kun Lee
AU  - Allison S.Y. Chan
AU  - Steven Blum
AU  - Chang Li
AU  - Haoran Ma
AU  - Wenyi Luo
AU  - Supriya Srivastava
AU  - Huey Yew Jeffrey Lum
AU  - Sheng Cong Norbert Tay
AU  - Woo Sun Kwon
AU  - Sejung Park
AU  - Craig Ryan Joseph
AU  - Li Yen Chong
AU  - Minkyu Jung
AU  - Shruti Sridhar
AU  - Aurelien Pelissier
AU  - Nilay Bhatt
AU  - Jia-Ying Joey Lee
AU  - Yichen Dai
AU  - Lit-Hsin Loo
AU  - Angie Lay Keng Tan
AU  - Takeshi Hagihara
AU  - Felicia Wee
AU  - Daryl K.A. Chia
AU  - Kevin M.S. Sim
AU  - Ming Teh
AU  - Izuma Nakayama
AU  - Jierui Xu
AU  - Matthew Chau Hsien Ng
AU  - Robert Walsh
AU  - Joe Poh Sheng Yeong
AU  - Anand D. Jeyasekharan
AU  - Heike I. Grabsch
AU  - Jimmy Bok-Yan So
AU  - Wei Peng Yong
AU  - Ignacio Vazquez-Garcia
AU  - Lloyd Bod
AU  - Samuel J. Klempner
AU  - Kohei Shitara
AU  - Yelena Janjigian
AU  - Patrick Tan
AU  - María Rodríguez Martínez
AU  - Sun Young Rha
AU  - Raghav Sundar
PY  - 2026
DA  - 2026/08/07
JO  - Clinical Cancer Research
DO  - 10.1158/1078-0432.ccr-26-1382
UR  - https://doi.org/10.1158/1078-0432.ccr-26-1382
AB  - 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.  Experimental 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).  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 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.  Conclusions:: 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.
SN  - 1078-0432
SN  - 1557-3265
ER  -