CD8 + T cell metabolism and function are suppressed by long-chain fatty acid uptake from the bone marrow microenvironment in Multiple Myeloma

Abstract

Abstract Background Multiple Myeloma (MM) is a plasma cell malignancy that develops in the bone marrow. Function of T lymphocytes is impaired in patients with MM and the bone marrow microenvironment is described as hostile for T cell activity. Precise suppressive mechanisms within the bone marrow microenvironment remain poorly defined but will impact efficacy of bispecific T cell engager and chimeric antigen receptor (CAR) T cell therapies. Methods In this study T cell phenotype, function and metabolic activity were analysed within paired bone marrow aspirate and peripheral blood samples from 72 patients across the spectrum of MM, including individuals with premalignant and asymptomatic disease, alongside age-matched controls. This permitted assessment of effects of disease stage and the bone marrow microenvironment. The bone marrow microenvironment was also modelled in vitro using autologous plasma co-culture systems. Results Bone marrow CD8+ T cell function decreased with MM development and was consistently lower within bone marrow samples than matched peripheral blood. These changes were accompanied by decreased mitochondrial mass, which correlated tightly with T cell function. Conversely, long-chain fatty acid uptake and peroxidation was markedly elevated in bone marrow CD8+ T cells. In vitro modelling confirmed uptake of bone marrow lipids suppresses CD8+ T function, which was impaired in autologous bone marrow plasma, but rescued by both lipid removal and inhibition of lipid peroxidation. Analysis of single-cell RNA-sequencing data identified expression of fatty acid transport protein 1 (FATP1) in bone marrow CD8+ T cells in MM, and FATP1 blockade also rescued CD8+ T cell function. Finally, analysis of samples from treated patient cohorts identified CD8+ T cell metabolic dysfunction resolves in treatment-responsive but not relapsed MM patients and is associated with substantial functional restoration. Conclusions CD8+ T cells are functionally impaired within the MM bone marrow microenvironment. This is accompanied by decreased mitochondrial mass but elevated uptake of long-chain fatty acids. Blockade of FATP1 restores CD8+ T cell function in presence of BM lipids and may therefore represent a novel therapeutic target to augment their activity in the bone marrow in MM and improve efficacy of T cell-directed therapies.