Interferon regulatory factor 8-driven reprogramming of the immune microenvironment enhances antitumor adaptive immunity and reduces immunosuppression in murine glioblastoma

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2024-12, Vol.26 (12), p.2272-2287
• Main Authors: Montoya, Megan, Collins, Sara A, Chuntova, Pavlina, Patel, Trishna S, Nejo, Takahide, Yamamichi, Akane, Kasahara, Noriyuki, Okada, Hideho
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Animals; Brain Neoplasms - immunology; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cellular Reprogramming; Dendritic Cells - immunology; Glioblastoma - immunology; Glioblastoma - metabolism; Glioblastoma - pathology; Immune Tolerance; Interferon Regulatory Factors - metabolism; Mice; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - metabolism; Tumor Microenvironment - immunology
• ISSN: 1522-8517; 1523-5866; 1523-5866
• DOI: 10.1093/neuonc/noae149

Glioblastoma (GBM) has a highly immunosuppressive tumor immune microenvironment (TIME), largely mediated by myeloid-derived suppressor cells (MDSCs). Here, we utilized a retroviral replicating vector (RRV) to deliver Interferon Regulatory Factor 8 (IRF8), a master regulator of type 1 conventional dendritic cell (cDC1) development, in a syngeneic murine GBM model. We hypothesized that RRV-mediated delivery of IRF8 could "reprogram" intratumoral MDSCs into antigen-presenting cells and thereby restore T-cell responses. Effects of RRV-IRF8 on survival and tumor growth kinetics were examined in the SB28 murine GBM model. The immunophenotype was analyzed by flow cytometry and gene expression assays. We assayed functional immunosuppression and antigen presentation by ex vivo T-cell-myeloid co-culture. Intratumoral injection of RRV-IRF8 in mice bearing intracerebral SB28 glioma significantly suppressed tumor growth and prolonged survival. RRV-IRF8 treated tumors exhibited significant enrichment of cDC1s and CD8+ T-cells. Additionally, myeloid cells derived from RRV-IRF8 tumors showed decreased expression of the immunosuppressive markers Arg1 and IDO1 and demonstrated reduced suppression of naïve T-cell proliferation in ex vivo co-culture, compared to controls. Furthermore, DCs from RRV-IRF8 tumors showed increased antigen presentation compared to those from control tumors. In vivo treatment with azidothymidine (AZT), a viral replication inhibitor, showed that IRF8 transduction in both tumor and non-tumor cells is necessary for survival benefit, associated with a reprogrammed, cDC1- and CD8 T-cell-enriched TIME. Our results indicate that reprogramming of glioma-infiltrating myeloid cells by in vivo expression of IRF8 may reduce immunosuppression and enhance antigen presentation, achieving improved tumor control.