ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Direct and indirect effects of cytomegalovirus infection on the graft-versus-leukaemia response (#128)

Alda Saldan 1 , Paulo Martins 2 , Ping Zhang 1 , Rachel Kuns 2 , Benjamin McEnroe 1 , Adaeze Ekwe 1 , Andrea Henden 1 , Rebecca Johnston 3 , Nic Waddell 3 , Steven Lane 4 5 , Peter Fleming 6 , Christopher Andoniou 6 7 , Mariapia Degli-Esposti 6 7 , Geoffrey Hill 2 5 8 , Siok-Keen Tey 1 5 8
  1. Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
  2. Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
  3. Medical Genomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
  4. Gordon and Jessie Gilmour Leukaemia Research Laboratory, QIMR Berghofer Medical Research Laboratory, Herston, QLD, Australia
  5. Royal Brisbane & Women's Hospital, Brisbane, QLD, Australia
  6. Centre for Experimental Immunology, Lyons Eye Institute, Perth, WA, Australia
  7. Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  8. Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia

Introduction. Human cytomegalovirus (CMV) is a major pathogen in allogeneic bone marrow transplantation (BMT), as post-transplant infection can lead to increased transplant-related mortality. However, CMV infection has also been associated with a reduced risk of acute myeloid leukaemia (AML) relapse after allogeneic BMT. The aim of this study is to investigate the effect of CMV infection on the graft-versus-leukaemia (GvL) response and to identify the mechanisms underpinning this effect.

Materials and Methods. We used a murine model of MHC-mismatched BMT to investigate the effect of CMV infection on the GvL effect. Mice were infected with murine CMV (MCMV) and, following viraemia clearance, used as either donors or recipients in allogeneic BMT. Lethally irradiated recipient mice were transplanted with donor BM and T cells, and challenged with GFP+ primary murine MLL-AF9 leukaemia. Recipients were monitored for graft-versus-host disease (GvHD), leukaemia burden and MCMV reactivation by clinical scoring, flow cytometry and qPCR, respectively. The direct effects of CMV on leukaemia were evaluated in vitro, infecting human Kasumi-3 AML cells, and in vivo on murine MLL-AF9 in BMT recipients. Phenotypic and transcriptomic changes in AML cells were evaluated by flow cytometry and RNA-seq, respectively.

Results and conclusions. Our results show that CMV has a multi-faceted impact on the GvL effect. Leukaemia survival was significantly improved in recipients of MCMV-seropositive donors versus MCMV-seronegative donors (median survival: 41 vs 31 days, p < 0.05).This stronger GvL effect was independent of NK cells but was associated with distinct transcriptomic profiles of CD8 T cells in spleen and BM. We demonstrated that in vitro CMV infection also induces phenotypic and transcriptomic changes in human Kasumi-3 AML cells, with downregulation of MHC-II and CD155 expression in CMV-infected AML cells, and increased expression of genes involved in type I interferon signaling and higher MHC-I surface expression in bystander AML.