Medicine (St Vincent's) - Research Publications

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Start date: 2020 × End date: 2022 × Author: Quach, Hang × Author: Harrison, Simon × Author: Ritchie, David ×

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    Myeloma natural killer cells are exhausted and have impaired regulation of activation
    D'Souza, C ; Keam, SP ; Yeang, HXA ; Neeson, M ; Richardson, K ; Hsu, AK ; Canfield, R ; Bezman, N ; Robbins, M ; Quach, H ; Ritchie, DS ; Harrison, SJ ; Trapani, JA ; Prince, HM ; Beavis, PA ; Darcy, PK ; Neeson, PJ (FERRATA STORTI FOUNDATION, 2021-09)
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    Conventional Treatment for Multiple Myeloma Drives Premature Aging Phenotypes and Metabolic Dysfunction in T Cells
    Cooke, RE ; Quinn, KM ; Quach, H ; Harrison, S ; Prince, HM ; Koldej, R ; Ritchie, D (FRONTIERS MEDIA SA, 2020-09-03)
    New diagnoses of multiple myeloma (MM) tend to occur after the age of 60, by which time thymic output is severely reduced. As a consequence, lymphocyte recovery after lymphopenia-inducing anti-MM therapies relies on homeostatic proliferation of peripheral T cells rather than replenishment by new thymic emigrants. To assess lymphocyte recovery and phenotype in patients with newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM), we tracked CD4+ and CD8+ T cell populations at serial time points throughout treatment and compared them to age-matched healthy donors (HD). Anti-MM therapies and autologous stem cell transplant (ASCT) caused a permanent reduction in the CD4:8 ratio, a decrease in naïve CD4+ T cells, and an increase in effector memory T cells and PD1-expressing CD4+ T cells. Transcriptional profiling highlighted that genes associated with fatty acid β-oxidation were upregulated in T cells in RRMM, suggesting increased reliance on mitochondrial respiration. High mitochondrial mass was seen in all T cell subsets in RRMM but with relatively suppressed reactive oxygen species and mitochondrial membrane potential, indicating mitochondrial dysfunction. These findings highlight that anti-MM and ASCT therapies perturb the composition of the T cell compartment and drive substantial metabolic remodeling, which may affect the fitness of T cells for immunotherapies. This is particularly pertinent to chimeric antigen receptor (CAR)-T therapy, which might be more efficacious if T cells were stored prior to ASCT rather than at relapse.