Conventional Treatment for Multiple Myeloma Drives Premature Aging Phenotypes and Metabolic Dysfunction in T Cells
Rachel E. Cooke, Kylie M. Quinn, Hang Quach, Simon J. Harrison, H. Miles Prince, Rachel Koldej, David Ritchie
Abstract
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 (NDMM) and relapsed/refractory (RRMM) MM, we tracked CD4+ and CD8+ T cell populations at serial timepoints throughout treatment, and compared to age-matched healthy donors (HD). Anti-MM therapies and autologous stem cell transplant (ASCT) caused a permanent reduction in CD4:8 ratio, a decrease in naïve CD4+ T cells with 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 remodelling, which may affect the fitness of T cells for immunotherapies.