Authors:

Alisha Bhatia

Date Created:

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About Paper:

recruitment in glioblastoma (GBM) Glioblastoma (GBM) is notably difficult to durably cure, due in part to the immunosuppressive GBM tumor microenvironment (TME). The long-range chemokine-mediated recruitment of cytotoxic T lymphocytes (CTL) is impaired by the glioma's production of immune-suppressive chemokines, preventing CTLs from infiltrating the tumor. To compensate for the CTL recruitment signal, we employ recombinant adeno-associated virus 6 (AAV6) expressing the lymphocyte trafficking chemokine C-X-C motif ligand 9 (CXCL9). We hypothesized this will transduce cells in the TME and enhance the call-and-receive signal for CTL recruitment, rendering GBMs more susceptible to anti- PD1 immune checkpoint blockade (ICB). AAV6's transduction was measured in vivo with 3D tissue and whole brain immunofluorescent imaging of tumor-bearing mice following intratumoral delivery of AAV6 encoding a fluorescent reporter. Cells from GL261 tumors treated with AAV6-CXCL9 were assessed with single cell RNA sequencing (scRNAseq) to examine lymphocyte infiltration. The therapeutic effect of AAV6-CXCL9 was assessed through survival studies of tumor model mice both treated and controlled. AAV6 transduction of tumor-associated astrocytes in the GBM TME was shown through tissue imaging. ScRNAseq data showed greater infiltration of CD8 T lymphocytes and T regulatory. In both KR158 and GL261 cell models, treatment with both AAV6-CXCL9 and aPD- 1 demonstrated a significant survival benefit. 254

Source:

University of Florida / 2024

Topics:

No topics listed

Co-authors:

Alisha Bhatia