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

Author

Listed:
  • Christina A. Roemeling

    (University of Florida
    University of Florida)

  • Jeet A. Patel

    (University of Florida
    University of Florida)

  • Savannah L. Carpenter

    (University of Florida
    University of Florida)

  • Oleg Yegorov

    (University of Florida
    University of Florida)

  • Changlin Yang

    (University of Florida
    University of Florida)

  • Alisha Bhatia

    (University of Florida
    University of Florida)

  • Bently P. Doonan

    (University of Florida
    University of Florida)

  • Rylynn Russell

    (University of Florida
    University of Florida)

  • Vrunda S. Trivedi

    (University of Florida
    University of Florida)

  • Kelena Klippel

    (University of Florida
    University of Florida)

  • Daniel H. Ryu

    (Emory University School of Medicine)

  • Adam Grippin

    (The University of Texas)

  • Hunter S. Futch

    (Emory University School of Medicine)

  • Yong Ran

    (Emory University School of Medicine)

  • Lan B. Hoang-Minh

    (University of Florida
    University of Florida)

  • Frances L. Weidert

    (University of Florida
    University of Florida)

  • Todd E. Golde

    (Emory University School of Medicine)

  • Duane A. Mitchell

    (University of Florida
    University of Florida)

Abstract

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.

Suggested Citation

  • Christina A. Roemeling & Jeet A. Patel & Savannah L. Carpenter & Oleg Yegorov & Changlin Yang & Alisha Bhatia & Bently P. Doonan & Rylynn Russell & Vrunda S. Trivedi & Kelena Klippel & Daniel H. Ryu &, 2024. "Adeno-associated virus delivered CXCL9 sensitizes glioblastoma to anti-PD-1 immune checkpoint blockade," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49989-1
    DOI: 10.1038/s41467-024-49989-1
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