ORCID Profile
0000-0003-0040-5617
Current Organisation
Monash University
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Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2019
DOI: 10.1158/2326-6066.CIR-18-0428
Abstract: Chimeric antigen receptor (CAR) T-cell therapy has proven successful in the treatment of hematological malignancies, notably acute lymphoblastic leukemia and B-cell lymphoma. However, the efficacy of CAR T cells against solid tumors is poor, likely due to tumor-associated immunosuppression. Here, we demonstrated that antagonizing the “inhibitor of apoptosis proteins” with the clinical smac-mimetic, birinapant, significantly enhanced the antitumor activity of CAR T cells in a tumor necrosis factor (TNF)-dependent manner. Enhanced tumor cell death occurred independently of the perforin-mediated granule exocytosis pathway, underscoring the cytotoxic potential of CAR T-cell–derived TNF. Combining CAR T-cell therapy with birinapant significantly reduced established tumor growth in vivo, where either therapy alone was relatively ineffective. Using patient biopsy-derived tumoroids, we demonstrated the synergistic potential of combining CAR T-cell therapy with smac-mimetics. Taken together, we identified CAR T-cell–derived TNF as a potent antitumor effector, which can be further harnessed by smac-mimetics.
Publisher: Springer Science and Business Media LLC
Date: 04-12-2020
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2326-6066.22539553.V1
Abstract: Movie S1
Publisher: Springer Science and Business Media LLC
Date: 30-06-2017
DOI: 10.1038/CDD.2017.94
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-05-2018
DOI: 10.1126/SCIIMMUNOL.AAR3451
Abstract: Whole-genome CRISPR screens identify resistance to TNF-mediated killing by T and NK cells as a tumor immune evasion mechanism.
Publisher: Springer Science and Business Media LLC
Date: 06-08-2021
DOI: 10.1038/S41467-021-25009-4
Abstract: The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control of metastatic B16F10 tumor growth relative to control mice. Analyses of this interplay in human tumor s les reveal that high expression of a MAIT cell gene signature negatively impacts the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or activating MAIT cells in vivo, enhances anti-tumor immunity in B16F10 and E0771 mouse tumor models, including in the context of established metastasis. These effects are associated with enhanced NK cell responses and increased expression of both IFN-γ-dependent and inflammatory genes in NK cells. Importantly, activated human MAIT cells also promote the function of NK cells isolated from patient tumor s les. Our results thus describe an activation-dependent, MAIT cell-mediated regulation of NK cells, and suggest a potential therapeutic avenue for cancer treatment.
Publisher: F1000 Research Ltd
Date: 27-01-2017
DOI: 10.12688/F1000RESEARCH.10117.1
Abstract: Hypertension, or high blood pressure, is a prevalent yet modifiable risk factor for cardiovascular disease. While there are many effective treatments available to combat hypertension, patients often require at least two to three medications to control blood pressure, although there are patients who are resistant to such therapies. This short review will briefly update on recent clinical advances and potential emerging therapies and is intended for a cross-disciplinary readership.
Publisher: EMBO
Date: 09-2021
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.CELREP.2019.08.017
Abstract: Despite the clinical success of cancer immunotherapies, the majority of patients fail to respond or develop resistance through disruption of pathways that promote neo-antigen presentation on MHC I molecules. Here, we conducted a series of unbiased, genome-wide CRISPR/Cas9 screens to identify genes that limit natural killer (NK) cell anti-tumor activity. We identified that genes associated with antigen presentation and/or interferon-γ (IFN-γ) signaling protect tumor cells from NK cell killing. Indeed, Jak1-deficient melanoma cells were sensitized to NK cell killing through attenuated NK cell-derived IFN-γ-driven transcriptional events that regulate MHC I expression. Importantly, tumor cells that became resistant to T cell killing through enrichment of MHC I-deficient clones were highly sensitive to NK cell killing. Taken together, we reveal the genes targeted by tumor cells to drive checkpoint blockade resistance but simultaneously increase their vulnerability to NK cells, unveiling NK cell-based immunotherapies as a strategy to antagonize tumor immune escape.
Publisher: Elsevier BV
Date: 10-1999
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2326-6066.22539547.V1
Abstract: Movie S2
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2326-6066.22539547
Abstract: Movie S2
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2326-6066.22539553
Abstract: Movie S1
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2326-6066.22539541
Abstract: Figures S1 and S2
Publisher: Elsevier BV
Date: 12-2021
Publisher: The American Association of Immunologists
Date: 15-09-2017
Abstract: Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause an autosomal recessive form of hyper-IgE syndrome, characterized by chronic immunodeficiency with persistent microbial infection and increased incidence of malignancy. These manifestations suggest a defect in cytotoxic lymphocyte function and immune surveillance. However, how DOCK8 regulates NK cell–driven immune responses remains unclear. In this article, we demonstrate that DOCK8 regulates NK cell cytotoxicity and cytokine production in response to target cell engagement or receptor ligation. Genetic ablation of DOCK8 in human NK cells attenuated cytokine transcription and secretion through inhibition of Src family kinase activation, particularly Lck, downstream of target cell engagement or NKp30 ligation. PMA/Ionomycin treatment of DOCK8-deficient NK cells rescued cytokine production, indicating a defect proximal to receptor ligation. Importantly, NK cells from DOCK8-deficient patients had attenuated production of IFN-γ and TNF-α upon NKp30 stimulation. Taken together, we reveal a novel molecular mechanism by which DOCK8 regulates NK cell–driven immunity.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2326-6066.22539544
Abstract: Supplementary data legends
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2326-6066.22539544.V1
Abstract: Supplementary data legends
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2326-6066.22539541.V1
Abstract: Figures S1 and S2
Publisher: American Association for Cancer Research (AACR)
Date: 07-12-2018
DOI: 10.1158/2326-6066.C.6549121.V1
Abstract: Abstract Chimeric antigen receptor (CAR) T-cell therapy has proven successful in the treatment of hematological malignancies, notably acute lymphoblastic leukemia and B-cell lymphoma. However, the efficacy of CAR T cells against solid tumors is poor, likely due to tumor-associated immunosuppression. Here, we demonstrated that antagonizing the “inhibitor of apoptosis proteins” with the clinical smac-mimetic, birinapant, significantly enhanced the antitumor activity of CAR T cells in a tumor necrosis factor (TNF)-dependent manner. Enhanced tumor cell death occurred independently of the perforin-mediated granule exocytosis pathway, underscoring the cytotoxic potential of CAR T-cell–derived TNF. Combining CAR T-cell therapy with birinapant significantly reduced established tumor growth i in vivo, /i where either therapy alone was relatively ineffective. Using patient biopsy-derived tumoroids, we demonstrated the synergistic potential of combining CAR T-cell therapy with smac-mimetics. Taken together, we identified CAR T-cell–derived TNF as a potent antitumor effector, which can be further harnessed by smac-mimetics. /
No related grants have been discovered for Andrew Freeman.