Poster Presentation 36th Lorne Cancer Conference 2024

Targeted Inhibition of Myeloperoxidase (MPO): A New Therapeutic Strategy for the Treatment of Multiple Myeloma (#241)

Connor MD Williams 1 2 , Jacqueline E Noll 1 2 , Alanah L Bradey 1 2 , Dylan Harnas 1 2 , Vicki J Wilczek 1 2 , Makutiro G Masavuli 3 , Branka Grubor-Bauk 3 , Romana A Panagopoulos 4 , Duncan Hewett 1 2 , Krzystof M Mrozik 1 2 , Kaitlin Wylie 5 6 , Andrew CW Zannettino 1 2 , Kate Vandyke 1 2 , Thomas R Cox 5 6 , Vasilios Panagopoulos 1 2
  1. Myeloma Research Laboratory, Faculty of Health and Medical Sciences, School of Biomedicine, University of Adelaide, Adelaide, SA, Australia
  2. Solid Tumour Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
  3. Viral Immunology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Health Research, University of Adelaide, Adelaide, SA, Australia
  4. Breast Cancer Research Unit, Discipline of Surgery, Basil Hetzel Institute for Translational Health Research, University of Adelaide, Adelaide, SA, Australia
  5. Matrix & Metastasis Lab, The Garvan Institute of Medical Research & the Kinghorn Cancer Centre, Cancer Ecosystems Program, Sydney, NSW, Australia
  6. School of Clinical Medicine, St Vincent’s Healthcare Clinical Campus, Faculty of Medicine and Health, UNSW , Sydney, NSW, Australia

Multiple myeloma (MM) is an aggressive haematological malignancy, characterised by the uncontrolled proliferation of monoclonal plasma cells (PC) within the bone marrow (BM). Recent studies have highlighted the critical role of the BM microenvironment in regulating myeloma immune evasion, disease progression and persistence. Myeloid-derived suppressor cells (MDSC), a heterogenous population of activated myeloid cells have been described as promoters of MM progression through immunosuppression. Myeloperoxidase (MPO), a key inflammatory enzyme important in host defence, is reported to be the most highly upregulated gene in MDSCs. Thus, the accumulation of MPO within the tumour microenvironment has gained considerable attention over recent years with reports describing MPO in regulating lung and breast cancer progression.
However, to date, the functional consequences of myeloid-derived MPO in MM disease progression is unknown. Here, we investigate for the first time the role of MPO in the MM microenvironment, and evaluate the pharmacological inhibition of MPO to impede MM progression.
In two well-characterised mouse models of MM that exhibit either an aggressive (KaLwRij/5TGM1) or latent (Vk*Myc/C57/Bl6) phenotype of disease progression, we confirmed that CD11b+ myeloid-derived cell populations are increased in the BM of MM tumour-bearing mice, accompanied by an increase in MPO expression and activity, during early tumour development. Mechanistically, MPO induced the expression of key MM growth factors, including IL-6, resulting in increased MM tumour cell proliferation (p<0.05). Furthermore, MPO pre-treatment of human T-cells significantly suppressed T-cell cytotoxicity towards human RPMI-8226 MM cells (p<0.01), while murine splenocytes pre-treated with MPO exhibited a significant reduction in antigen-specific IFN-γ responses, crucial for anti-tumour activity (p<0.01).
Notably, tumour growth studies in both the aggressive and latent mouse models of MM treated with small-molecule irreversible inhibitors of MPO, demonstrated a significant reduction in overall MM tumour burden by 52% (p<0.05) and 15% (p<0.01) respectively.
Taken together, we demonstrate for the first time, that MPO is highly up-regulated in the myeloma microenvironment from early stage of disease, promoting immune suppression and tumour growth, and that MPO-specific inhibitors may provide a new therapeutic strategy to limit MM disease progression.