Adeno-associated virus delivered CXCL9 sensitizes glioblastoma to anti-PD-1 immune checkpoint blockade

• Published in: Nature communications Vol. 15; no. 1; pp. 5871 - 20
• Main Authors: von Roemeling, Christina A., Patel, Jeet A., Carpenter, Savannah L., Yegorov, Oleg, Yang, Changlin, Bhatia, Alisha, Doonan, Bently P., Russell, Rylynn, Trivedi, Vrunda S., Klippel, Kelena, Ryu, Daniel H., Grippin, Adam, Futch, Hunter S., Ran, Yong, Hoang-Minh, Lan B., Weidert, Frances L., Golde, Todd E., Mitchell, Duane A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.07.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/31; 13/51; 42; 42/35; 42/44; 45; 45/91; 49; 49/79; 59; 631/67/1059/2325; 631/67/1922; 64; 692/4028/67/580; Animals; Brain; Brain Neoplasms - immunology; Brain Neoplasms - therapy; Brain tumors; Cell activation; Cell culture; Cell Line, Tumor; Chemokine CXCL9 - genetics; Chemokine CXCL9 - immunology; Chemokines; Combinatorial analysis; Cytotoxicity; Dependovirus - genetics; Female; Gene therapy; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Glioblastoma; Glioblastoma - immunology; Glioblastoma - therapy; Glioblastoma cells; Glioma; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - therapeutic use; Immunogenicity; Immunology; Infiltration; Inflammation; Leukocyte migration; Lymphocytes; Lymphocytes T; Metastases; Mice; Modularity; multidisciplinary; PD-1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Reconditioning; Science; Science (multidisciplinary); Sensitizing; Tropism; Tumor microenvironment; Tumor Microenvironment - immunology; Tumors; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49989-1

There are numerous mechanisms by which glioblastoma cells evade immunological detection, underscoring the need for strategic combinatorial treatments to achieve appreciable therapeutic effects. However, developing combination therapies is difficult due to dose-limiting toxicities, blood-brain-barrier, and suppressive tumor microenvironment. Glioblastoma is notoriously devoid of lymphocytes driven in part by a paucity of lymphocyte trafficking factors necessary to prompt their recruitment and activation. Herein, we develop a recombinant adeno-associated virus (AAV) gene therapy that enables focal and stable reconstitution of the tumor microenvironment with C-X-C motif ligand 9 (CXCL9), a powerful call-and-receive chemokine for lymphocytes. By manipulating local chemokine directional guidance, AAV-CXCL9 increases tumor infiltration by cytotoxic lymphocytes, sensitizing glioblastoma to anti-PD-1 immune checkpoint blockade in female preclinical tumor models. These effects are accompanied by immunologic signatures evocative of an inflamed tumor microenvironment. These findings support AAV gene therapy as an adjuvant for reconditioning glioblastoma immunogenicity given its safety profile, tropism, modularity, and off-the-shelf capability. The limited infiltration and migration of T cells in the brain can hinder the success of immune checkpoint blockade in glioblastoma (GBM). Here the authors show that an adeno-associated virus-based gene therapy for the intratumor delivery of CXCL9 promotes T cell infiltration and enhances response to anti-PD1 in GBM preclinical models.