Concise review: The heterogenous roles of BATF3 in cancer oncogenesis and dendritic cells and T cells differentiation and function considering the importance of BATF3-dependent dendritic cells

Dabbaghipour, Reza; Ahmadi, Elham; Entezam, Mona; Farzam, Omid Rahbar; Sohrabi, Sepideh; Jamali, Sajjad; Sichani, Ali Saber; Paydar, Hadi; Baradaran, Behzad

doi:10.1007/s00251-024-01335-x

Cited by 4 publications

(1 citation statement)

References 128 publications

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“…S2b). The importance of antigen cross-presentation by cDC1s in potentiating anti-tumor immunity is well-reviewed in the literature, and multiple studies have shown that even a modest increase in intra-tumoral cDC1s can significantly enhance T-cell mediating tumor killing 37,52,53…”

Section: Discussionmentioning

confidence: 99%

IRF8-driven reprogramming of the immune microenvironment enhances anti-tumor adaptive immunity and reduces immunosuppression in murine glioblastoma

Montoya,

Collins,

Chuntova

et al. 2024

Preprint

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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 (APCs) and thereby restore T-cell responses. Effects of RRV-IRF8 on survival and tumor growth kinetics were examined in the SB28 murine GBM model. 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. Mice with RRV-IRF8 pre-transduced intracerebral tumors had significantly longer survival and slower tumor growth compared to controls. 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 naive 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.

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Section: Discussionmentioning

confidence: 99%

IRF8-driven reprogramming of the immune microenvironment enhances anti-tumor adaptive immunity and reduces immunosuppression in murine glioblastoma

Montoya,

Collins,

Chuntova

et al. 2024

Preprint

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Oral N-acetylcysteine ameliorates liver fibrosis and enhances regenerative responses in Mdr2 knockout mice

Har-Zahav,

Tobar,

Fried

et al. 2024

Sci Rep

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Cholangiopathies are poorly understood disorders with no effective therapy. The extrahepatic biliary tree phenotype is less studied compared to the intrahepatic biliary injury in both human disease and Mdr2 −/− mice, the established cholestatic mouse model. This study aimed to characterize the extra hepatic biliary tree of Mdr2 −/− mice at various ages and to determine if injury can be repaired with the antioxidant and glutathione precursor N -acetyl- L -Cysteine treatment (NAC). We characterized extra hepatic bile ducts (EHBD)s at various ages from 2 to 40 weeks old FVB/N and Mdr2 −/− mice. We examined the therapeutic potential of local NAC ex vivo using EHBD explants at early and late stages of injury; and systematic therapy by in vivo oral administration for 3 weeks. EHBD and liver sections were assessed by histology and immunofluorescent stains. Serum liver enzyme activities were analyzed, and liver spatial protein expression analysis was performed. Mdr2 −/− mice developed progressive EHBD injury, similar to extrahepatic PSC. NAC treatment of ex vivo EHBD explants led to improved duct morphology. In vivo, oral administration of NAC improved liver fibrosis, and decreased liver enzyme activities. Spatial protein analysis revealed cell-type specific differential response to NAC, collectively indicating a transition from pro-apoptotic into proliferative state. NAC treatment should be further investigated as a potential therapeutic option for human cholangiopathies. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-78387-2.

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

Montoya,

Collins,

Chuntova

et al. 2024

Neuro-Oncology

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Background 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 (APCs) and thereby restore T-cell responses. Methods Effects of RRV-IRF8 on survival and tumor growth kinetics were examined in the SB28 murine GBM model. 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. Results Intratumoral injection of RRV-IRF8 in mice bearing intracerebral SB28 glioma significantly suppressed the 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. Conclusions 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.

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Concise review: The heterogenous roles of BATF3 in cancer oncogenesis and dendritic cells and T cells differentiation and function considering the importance of BATF3-dependent dendritic cells

Cited by 4 publications

References 128 publications

IRF8-driven reprogramming of the immune microenvironment enhances anti-tumor adaptive immunity and reduces immunosuppression in murine glioblastoma

IRF8-driven reprogramming of the immune microenvironment enhances anti-tumor adaptive immunity and reduces immunosuppression in murine glioblastoma

Oral N-acetylcysteine ameliorates liver fibrosis and enhances regenerative responses in Mdr2 knockout mice

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

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