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ELTD1 deletion reduces vascular abnormality and improves T-cell recruitment after PD-1 blockade in glioma.
Huang, Hua; Georganaki, Maria; Conze, Lei Liu; Laviña, Bàrbara; van Hooren, Luuk; Vemuri, Kalyani; van de Walle, Tiarne; Ramachandran, Mohanraj; Zhang, Lei; Pontén, Fredrik; Bergqvist, Michael; Smits, Anja; Betsholtz, Christer; Dejana, Elisabetta; Magnusson, Peetra U; He, Liqun; Lugano, Roberta; Dimberg, Anna.
Afiliación
  • Huang H; Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Georganaki M; Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Conze LL; Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Laviña B; Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • van Hooren L; Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Vemuri K; Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • van de Walle T; Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Ramachandran M; Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Zhang L; Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, China.
  • Pontén F; Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Bergqvist M; Center for Research and Development, Gävle Hospital, Uppsala University, Gävle, Sweden.
  • Smits A; Department of Radiation Sciences and Oncology, Umeå University Hospital, Umeå, Sweden.
  • Betsholtz C; Department of Clinical Neuroscience, Sahlgrenska Academy, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
  • Dejana E; Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Magnusson PU; Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • He L; Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Lugano R; Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Dimberg A; Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Neuro Oncol ; 24(3): 398-411, 2022 03 12.
Article en En | MEDLINE | ID: mdl-34347079
BACKGROUND: Tumor vessels in glioma are molecularly and functionally abnormal, contributing to treatment resistance. Proteins differentially expressed in glioma vessels can change vessel phenotype and be targeted for therapy. ELTD1 (Adgrl4) is an orphan member of the adhesion G-protein-coupled receptor family upregulated in glioma vessels and has been suggested as a potential therapeutic target. However, the role of ELTD1 in regulating vessel function in glioblastoma is poorly understood. METHODS: ELTD1 expression in human gliomas and its association with patient survival was determined using tissue microarrays and public databases. The role of ELTD1 in regulating tumor vessel phenotype was analyzed using orthotopic glioma models and ELTD1-/- mice. Endothelial cells isolated from murine gliomas were transcriptionally profiled to determine differentially expressed genes and pathways. The consequence of ELTD1 deletion on glioma immunity was determined by treating tumor-bearing mice with PD-1-blocking antibodies. RESULTS: ELTD1 levels were upregulated in human glioma vessels, increased with tumor malignancy, and were associated with poor patient survival. Progression of orthotopic gliomas was not affected by ELTD1 deletion, however, tumor vascular function was improved in ELTD1-/- mice. Bioinformatic analysis of differentially expressed genes indicated increased inflammatory response and decreased proliferation in tumor endothelium in ELTD1-/- mice. Consistent with an enhanced inflammatory response, ELTD1 deletion improved T-cell infiltration in GL261-bearing mice after PD-1 checkpoint blockade. CONCLUSION: Our data demonstrate that ELTD1 participates in inducing vascular dysfunction in glioma, and suggest that targeting of ELTD1 may normalize the vessels and improve the response to immunotherapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Receptores Acoplados a Proteínas G / Glioma Límite: Animals / Humans Idioma: En Revista: Neuro Oncol Asunto de la revista: NEOPLASIAS / NEUROLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Receptores Acoplados a Proteínas G / Glioma Límite: Animals / Humans Idioma: En Revista: Neuro Oncol Asunto de la revista: NEOPLASIAS / NEUROLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Reino Unido