Tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma.

Autor:	Ramachandran M; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., Vaccaro A; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., van de Walle T; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., Georganaki M; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., Lugano R; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., Vemuri K; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., Kourougkiaouri D; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., Vazaios K; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., Hedlund M; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., Tsaridou G; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., Uhrbom L; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., Pietilä I; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., Martikainen M; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., van Hooren L; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., Olsson Bontell T; Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; Department of Clinical Pathology, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden., Jakola AS; Department of Neurosurgery, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden; Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden., Yu D; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., Westermark B; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., Essand M; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden. Electronic address: magnus.essand@igp.uu.se., Dimberg A; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden. Electronic address: anna.dimberg@igp.uu.se.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2023 Jun 12; Vol. 41 (6), pp. 1134-1151.e10. Date of Electronic Publication: 2023 May 11.
DOI:	10.1016/j.ccell.2023.04.010
Abstrakt:	Glioblastomas are aggressive brain tumors that are largely immunotherapy resistant. This is associated with immunosuppression and a dysfunctional tumor vasculature, which hinder T cell infiltration. LIGHT/TNFSF14 can induce high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), suggesting that its therapeutic expression could promote T cell recruitment. Here, we use a brain endothelial cell-targeted adeno-associated viral (AAV) vector to express LIGHT in the glioma vasculature (AAV-LIGHT). We found that systemic AAV-LIGHT treatment induces tumor-associated HEVs and T cell-rich TLS, prolonging survival in αPD-1-resistant murine glioma. AAV-LIGHT treatment reduces T cell exhaustion and promotes TCF1 + CD8 + stem-like T cells, which reside in TLS and intratumoral antigen-presenting niches. Tumor regression upon AAV-LIGHT therapy correlates with tumor-specific cytotoxic/memory T cell responses. Our work reveals that altering vascular phenotype through vessel-targeted expression of LIGHT promotes efficient anti-tumor T cell responses and prolongs survival in glioma. These findings have broader implications for treatment of other immunotherapy-resistant cancers. Competing Interests: Declaration of interests M.R., A.V., T.v.d.W., M.E., and A.D. have filed a patent application for using an AAV to deliver the LIGHT gene to tumor endothelial cells. The patent application includes examples from the article. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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