High AXL Expression and Stromal–Angiogenic Immune Phenotypes in Upper Gastrointestinal Cancers

AXL, a receptor tyrosine kinase, has been implicated in epithelial-mesenchymal transition, angiogenesis, immune evasion, and therapeutic resistance, but its relevance in upper gastrointestinal cancers remains incompletely defined. We analyzed 337 patients with advanced gastric (n = 287) or esophageal (n = 50) cancer enrolled in SCRUM-Japan MONSTAR-SCREEN-2, whose tumors were profiled by whole-exome and whole-transcriptome sequencing. Patients were classified as AXL-high (n = 169) or AXL-low (n = 168) using cancer type-specific median transcripts-per-million cutoffs. Median follow-up was 14.1 months. AXL-high tumors were associated with shorter overall survival than AXL-low tumors (median, 12.9 versus 17.1 months; hazard ratio, 1.58; 95% confidence interval, 1.17-2.14; p = 0.003), consistently in gastric (hazard ratio, 1.47; p = 0.020) and esophageal (hazard ratio, 2.46; p = 0.027) cancer. This association persisted after adjustment for cancer type, age, sex, number of metastatic sites, microsatellite instability status, and tumor mutational burden (hazard ratio, 1.59; 95% confidence interval, 1.14-2.22; p = 0.007). Among microsatellite stable patients treated with immune checkpoint blockade, AXL expression was not associated with progression-free survival (hazard ratio, 0.83; 95% confidence interval, 0.61-1.14; p = 0.255). AXL-high tumors showed stromal and vascular expansion, regulatory T-cell enrichment, higher expression of fibroblast growth factor receptor 1, vascular endothelial growth factor receptors 1-3, and MET, and enrichment of epithelial-mesenchymal transition, angiogenesis, and transforming growth factor beta signaling. High AXL expression identifies a poor-prognosis stromal-angiogenic phenotype in upper gastrointestinal cancers and warrants prospective validation as a prognostic, rather than predictive, biomarker. Trial Registration: UMIN Clinical Trials Registry, UMIN000043899.

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Journal
Cancer Science
Published
2026-11-11
DOI
https://doi.org/10.1111/cas.70594
Primary Topic
Cancer Immunotherapy and Biomarkers
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article
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article

High AXL Expression and Stromal–Angiogenic Immune Phenotypes in Upper Gastrointestinal Cancers

Toshihiro Kudo, Chigusa Morizane, Akihito Tsuji, Taro Shibuki et al.
Cancer Science
Cancer Immunotherapy and Biomarkers
article

High AXL Expression and Stromal–Angiogenic Immune Phenotypes in Upper Gastrointestinal Cancers

Toshihiro Kudo, Chigusa Morizane, Akihito Tsuji, Taro Shibuki, Kyosuke Seguchi, Tadayoshi Hashimoto, Fumio Nagashima, Kentaro Yamazaki, Hideaki Bando, Karam Ashouri, Shigenori Kadowaki, Takao Fujisawa, Yoshito Komatsu, Shogen Boku, Taroh Satoh, Sandra D. Algaze, Takayuki Yoshino, Eiji Oki, Koushiro Ohtsubo, Naoko Iida, Yohei Kubota, Akitaka Makiyama, Naoki Takahashi, Heinz Josef Lenz, Yukiko Fukuda, Takeshi Kato
article en

Abstract

AXL, a receptor tyrosine kinase, has been implicated in epithelial-mesenchymal transition, angiogenesis, immune evasion, and therapeutic resistance, but its relevance in upper gastrointestinal cancers remains incompletely defined. We analyzed 337 patients with advanced gastric (n = 287) or esophageal (n = 50) cancer enrolled in SCRUM-Japan MONSTAR-SCREEN-2, whose tumors were profiled by whole-exome and whole-transcriptome sequencing. Patients were classified as AXL-high (n = 169) or AXL-low (n = 168) using cancer type-specific median transcripts-per-million cutoffs. Median follow-up was 14.1 months. AXL-high tumors were associated with shorter overall survival than AXL-low tumors (median, 12.9 versus 17.1 months; hazard ratio, 1.58; 95% confidence interval, 1.17-2.14; p = 0.003), consistently in gastric (hazard ratio, 1.47; p = 0.020) and esophageal (hazard ratio, 2.46; p = 0.027) cancer. This association persisted after adjustment for cancer type, age, sex, number of metastatic sites, microsatellite instability status, and tumor mutational burden (hazard ratio, 1.59; 95% confidence interval, 1.14-2.22; p = 0.007). Among microsatellite stable patients treated with immune checkpoint blockade, AXL expression was not associated with progression-free survival (hazard ratio, 0.83; 95% confidence interval, 0.61-1.14; p = 0.255). AXL-high tumors showed stromal and vascular expansion, regulatory T-cell enrichment, higher expression of fibroblast growth factor receptor 1, vascular endothelial growth factor receptors 1-3, and MET, and enrichment of epithelial-mesenchymal transition, angiogenesis, and transforming growth factor beta signaling. High AXL expression identifies a poor-prognosis stromal-angiogenic phenotype in upper gastrointestinal cancers and warrants prospective validation as a prognostic, rather than predictive, biomarker. Trial Registration: UMIN Clinical Trials Registry, UMIN000043899.

Cancer Science
University of Southern California (US), Kansai Medical University (JP), Tokyo University of Science (JP), St. Marianna University School of Medicine (JP), Kyorin University (JP), Kagawa University (JP), National Cancer Centre Japan (JP), Shizuoka Cancer Center (JP), Osaka National Hospital (JP), Kyushu University Hospital (JP), Kanazawa University Hospital (JP), Gifu University Hospital (JP), USC Norris Comprehensive Cancer Center (US), Saitama Cancer Center (JP), Aichi Cancer Center (JP), Kagawa University Hospital (JP), Hokkaido University Hospital (JP), National Cancer Center Hospital East (JP), Osaka International Cancer Institute (JP), Osaka University Hospital (JP), Kansai Medical University Hospital (JP), National Cancer Center Hospital (JP), Aichi Cancer Center Hospital (JP), The University of Osaka (JP)
Cancer Immunotherapy and Biomarkers
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