Spatial proteomics identifies a spectrum of immune dysregulation in acquired bone marrow failure syndromes

Poor graft function (PGF), manifested by multilineage cytopenias and complete donor chimerism post-allogeneic stem cell transplantation (alloSCT), and acquired aplastic anaemia (AA) are immune-mediated acquired bone marrow (BM) failure syndromes with a similar clinical presentation. In this study, w...

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Published inFrontiers in immunology Vol. 14; p. 1213560
Main Authors Koldej, Rachel M., Prabahran, Ashvind, Tan, Chin Wee, Ludford-Menting, Mandy, Morgan, Huw, Holzwart, Nicholas, Davis, Melissa J., Ritchie, David S.
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Published Frontiers Media S.A 25.09.2023
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Abstract Poor graft function (PGF), manifested by multilineage cytopenias and complete donor chimerism post-allogeneic stem cell transplantation (alloSCT), and acquired aplastic anaemia (AA) are immune-mediated acquired bone marrow (BM) failure syndromes with a similar clinical presentation. In this study, we used spatial proteomics to compare the immunobiology of the BM microenvironment and identify common mechanisms of immune dysregulation under these conditions. Archival BM trephines from patients exhibited downregulation of the immunoregulatory protein VISTA and the M2 macrophage marker and suppressor of T-cell activation ARG1 with increased expression of the immune checkpoint B7-H3 compared to normal controls. Increased CD163 and CD14 expression suggested monocyte/macrophage skewing, which, combined with dysregulation of STING and VISTA, is indicative of an environment of reduced immunoregulation resulting in the profound suppression of hematopoiesis in these two conditions. There were no changes in the immune microenvironment between paired diagnostic AA and secondary MDS/AML samples suggesting that leukaemic clones develop in the impaired immune microenvironment of AA without the need for further alterations. Of the eight proteins with dysregulated expression shared by diagnostic AA and PGF, the diagnostic AA samples had a greater fold change in expression than PGF, suggesting that these diseases represent a spectrum of immune dysregulation. Unexpectedly, analysis of samples from patients with good graft function post-alloSCT demonstrated significant changes in the immune microenvironment compared to normal controls, with downregulation of CD44, STING, VISTA, and ARG1, suggesting that recovery of multilineage haematopoiesis post-alloSCT does not reflect recovery of immune function and may prime patients for the development of PGF upon further inflammatory insult. The demonstrable similarities in the immunopathology of AA and PGF will allow the design of clinical interventions that include both patient cohorts to accelerate therapeutic discovery and translation.
AbstractList Poor graft function (PGF), manifested by multilineage cytopenias and complete donor chimerism post-allogeneic stem cell transplantation (alloSCT), and acquired aplastic anaemia (AA) are immune-mediated acquired bone marrow (BM) failure syndromes with a similar clinical presentation. In this study, we used spatial proteomics to compare the immunobiology of the BM microenvironment and identify common mechanisms of immune dysregulation under these conditions. Archival BM trephines from patients exhibited downregulation of the immunoregulatory protein VISTA and the M2 macrophage marker and suppressor of T-cell activation ARG1 with increased expression of the immune checkpoint B7-H3 compared to normal controls. Increased CD163 and CD14 expression suggested monocyte/macrophage skewing, which, combined with dysregulation of STING and VISTA, is indicative of an environment of reduced immunoregulation resulting in the profound suppression of hematopoiesis in these two conditions. There were no changes in the immune microenvironment between paired diagnostic AA and secondary MDS/AML samples suggesting that leukaemic clones develop in the impaired immune microenvironment of AA without the need for further alterations. Of the eight proteins with dysregulated expression shared by diagnostic AA and PGF, the diagnostic AA samples had a greater fold change in expression than PGF, suggesting that these diseases represent a spectrum of immune dysregulation. Unexpectedly, analysis of samples from patients with good graft function post-alloSCT demonstrated significant changes in the immune microenvironment compared to normal controls, with downregulation of CD44, STING, VISTA, and ARG1, suggesting that recovery of multilineage haematopoiesis post-alloSCT does not reflect recovery of immune function and may prime patients for the development of PGF upon further inflammatory insult. The demonstrable similarities in the immunopathology of AA and PGF will allow the design of clinical interventions that include both patient cohorts to accelerate therapeutic discovery and translation.
Author Ludford-Menting, Mandy
Koldej, Rachel M.
Ritchie, David S.
Morgan, Huw
Davis, Melissa J.
Prabahran, Ashvind
Tan, Chin Wee
Holzwart, Nicholas
AuthorAffiliation 6 Department of Clinical Pathology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne , Melbourne, VIC , Australia
2 Department of Medicine, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne , Melbourne, VIC , Australia
5 Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne , Melbourne, VIC , Australia
1 Australian Cancer Research Foundation (ACRF) Translational Research Laboratory, Royal Melbourne Hospital , Melbourne, VIC , Australia
4 Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research , Melbourne, VIC , Australia
3 Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital , Melbourne, VIC , Australia
AuthorAffiliation_xml – name: 1 Australian Cancer Research Foundation (ACRF) Translational Research Laboratory, Royal Melbourne Hospital , Melbourne, VIC , Australia
– name: 4 Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research , Melbourne, VIC , Australia
– name: 3 Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital , Melbourne, VIC , Australia
– name: 6 Department of Clinical Pathology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne , Melbourne, VIC , Australia
– name: 2 Department of Medicine, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne , Melbourne, VIC , Australia
– name: 5 Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne , Melbourne, VIC , Australia
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Copyright Copyright © 2023 Koldej, Prabahran, Tan, Ludford-Menting, Morgan, Holzwart, Davis and Ritchie 2023 Koldej, Prabahran, Tan, Ludford-Menting, Morgan, Holzwart, Davis and Ritchie
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Reviewed by: Roi Gazit, Ben Gurion University of the Negev, Israel; Marie-Dominique Filippi, Cincinnati Children’s Research Foundation, United States
Present address: Melissa J. Davis, South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA, Australia
Edited by: Minrui Liang, Fudan University, China
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Snippet Poor graft function (PGF), manifested by multilineage cytopenias and complete donor chimerism post-allogeneic stem cell transplantation (alloSCT), and acquired...
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SubjectTerms aplastic anaemia
bone marrow
Immunology
microenvironment
poor graft function
spatial proteomics
stem cell transplant
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Title Spatial proteomics identifies a spectrum of immune dysregulation in acquired bone marrow failure syndromes
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https://pubmed.ncbi.nlm.nih.gov/PMC10560754
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Volume 14
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