Sir Peter MacCallum Department of Oncology - Research Publications

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    CRISPR-Cas9 screening identifies an IRF1-SOCS1-mediated negative feedback loop that limits CXCL9 expression and antitumor immunity
    House, IG ; Derrick, EB ; Sek, K ; Chen, AXY ; Li, J ; Lai, J ; Todd, KL ; Munoz, I ; Michie, J ; Chan, CW ; Huang, Y-K ; Chan, JD ; Petley, E ; Tong, J ; Nguyen, D ; Engel, S ; Savas, P ; Hogg, SJ ; Vervoort, SJ ; Kearney, CJ ; Burr, ML ; Lam, EYN ; Gilan, O ; Bedoui, S ; Johnstone, RW ; Dawson, MA ; Loi, S ; Darcy, PK ; Beavis, PA (CELL PRESS, 2023-08-29)
    CXCL9 expression is a strong predictor of response to immune checkpoint blockade therapy. Accordingly, we sought to develop therapeutic strategies to enhance the expression of CXCL9 and augment antitumor immunity. To perform whole-genome CRISPR-Cas9 screening for regulators of CXCL9 expression, a CXCL9-GFP reporter line is generated using a CRISPR knockin strategy. This approach finds that IRF1 limits CXCL9 expression in both tumor cells and primary myeloid cells through induction of SOCS1, which subsequently limits STAT1 signaling. Thus, we identify a subset of STAT1-dependent genes that do not require IRF1 for their transcription, including CXCL9. Targeting of either IRF1 or SOCS1 potently enhances CXCL9 expression by intratumoral macrophages, which is further enhanced in the context of immune checkpoint blockade therapy. We hence show a non-canonical role for IRF1 in limiting the expression of a subset of STAT1-dependent genes through induction of SOCS1.
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    Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
    Salmon, JM ; Todorovski, I ; Stanley, KL ; Bruedigam, C ; Kearney, CJ ; Martelotto, LG ; Rossello, F ; Semple, T ; Arnau, GM ; Zethoven, M ; Bots, M ; Bjelosevic, S ; Cluse, LA ; Fraser, PJ ; Litalien, V ; Vidacs, E ; McArthur, K ; Matthews, AY ; Gressier, E ; de Weerd, NA ; Lichte, J ; Kelly, MJ ; Hogg, SJ ; Hertzog, PJ ; Kats, LM ; Vervoort, SJ ; De Carvalho, DD ; Scheu, S ; Bedoui, S ; Kile, BT ; Lane, SW ; Perkins, AC ; Wei, AH ; Dominguez, PM ; Johnstone, RW (AMER ASSOC CANCER RESEARCH, 2022-06)
    UNLABELLED: Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies. SIGNIFICANCE: We demonstrate that HDACis induce terminal differentiation of AML through epigenetic remodeling of pDCs, resulting in production of type I IFN that is important for the therapeutic effects of HDACis. The study demonstrates the important functional interplay between the immune system and leukemias in response to HDAC inhibition. This article is highlighted in the In This Issue feature, p. 1397.
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    Epigenetic reprogramming of plasmacytoid dendritic cells drives type I interferon-dependent differentiation of acute myeloid leukemias for therapeutic benefit
    Salmon, J ; Todorovski, I ; Vervoort, S ; Stanley, K ; Kearney, C ; Martelotto, L ; Rossello, F ; Semple, T ; Mir-Arnau, G ; Zethoven, M ; Bots, M ; Vidacs, E ; McArthur, K ; Gressier, E ; de Weerd, N ; Lichte, J ; Kelly, M ; Cluse, L ; Hogg, S ; Hertzog, P ; Kats, L ; de Carvalho, D ; Scheu, S ; Bedoui, S ; Kile, B ; Wei, A ; Dominguez, P ; Johnstone, R ( 2020-08-24)
    Pharmacological inhibition of epigenetic enzymes can have therapeutic benefit, particularly against hematological malignancies. While these agents can affect tumor cell growth and proliferation, recent studies have demonstrated that pharmacological de-regulation of epigenetic modifiers may additionally mediate anti-tumor immune responses. Here we discovered a novel mechanism of immune regulation through the inhibition of histone deacetylases (HDACs). In a genetically engineered model of t(8;21) AML, leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor panobinostat required activation of the type I interferon (IFN) signaling pathway. Plasmacytoid dendritic cells (pDCs) were identified as the cells producing type I IFN in response to panobinostat, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated activation of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, while combined treatment of panobinostat and recombinant IFNα improved therapeutic outcomes. These discoveries offer a new therapeutic approach for t(8;21) AML and demonstrate that epigenetic rewiring of pDCs enhances anti-tumor immunity, opening the possibility of exploiting this cell type as a new target for immunotherapy.