ORCID Profile
0000-0002-7974-0137
Current Organisation
University of South Australia
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Publisher: Elsevier BV
Date: 10-2023
Publisher: Elsevier BV
Date: 08-2019
Publisher: Rockefeller University Press
Date: 14-04-2020
DOI: 10.1084/JEM.20190634
Abstract: Current immunotherapies involving CD8+ T cell responses show remarkable promise, but their efficacy in many solid tumors is limited, in part due to the low frequency of tumor-specific T cells in the tumor microenvironment (TME). Here, we identified a role for host atypical chemokine receptor 4 (ACKR4) in controlling intratumor T cell accumulation and activation. In the absence of ACKR4, an increase in intratumor CD8+ T cells inhibited tumor growth, and nonhematopoietic ACKR4 expression was critical. We show that ACKR4 inhibited CD103+ dendritic cell retention in tumors through regulation of the intratumor abundance of CCL21. In addition, preclinical studies indicate that ACKR4 and CCL21 are potential therapeutic targets to enhance responsiveness to immune checkpoint blockade or T cell costimulation.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 08-07-2021
Publisher: American Society of Hematology
Date: 12-10-2023
DOI: 10.1182/BLOODADVANCES.2023010045
Abstract: In iduals with germline variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of pre-malignant states in HHMs have h ered efforts to design effective clinical surveillance programs, provide personalized pre-emptive treatments and inform appropriate counselling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies ("carriers-without HM"). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second-hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For ex le, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germline variants for the acquisition of somatic variants in BCOR, PHF6, TET2, and second hits in RUNX1 are warranted.
Publisher: American Society of Hematology
Date: 15-11-2022
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Mark Armstrong.