Aberrant metabolic processes promote the immunosuppressive microenvironment in multiple myeloma

Abstract

IntroductionMultiple myeloma (MM) is still an incurable plasma cell malignancy. The efficacy of immunotherapy on MM remains unsatisfactory, and the underlying molecular mechanisms still are not fully understood.MethodsIn this study, we delineated the dynamic features of immune cell in MM bone marrow (BM) along with elevated tumor cell infiltration by single-cell RNA sequencing (scRNA-seq), and investigated the underlying mechanisms on dysfunction of immune cells associated with myelomagenesis.ResultsWe found that immune cells were activated in those patients with low infiltration of tumor cells, meanwhile suppressed with elevated infiltration of MM cells, which facilitated MM escaping from immune surveillance. Besides PD-1, abnormal expression of PIM kinases, KLRB1 and KLRC1 were involved in the defect of immune cells in MM patients. Importantly, we found aberrant metabolic processes were associated with the immunosuppressive microenvironment in MM patients. Disordered amino acid metabolism promoted the dysfunction of cytotoxicity CD8 T cells as well as lipid metabolism disorder was associated with the dysregulation of NK and DCs in MM. As metabolic checkpoints, PIM kinases would be potential effective strategies for MM immunotherapy.DiscussionIn summary, redressing the disordered metabolism should be the key points to get promising effects in immune-based therapies.

Single-cell profiles reveal tumor cell heterogeneity and immunosuppressive microenvironment in Waldenström macroglobulinemia

“…However, the molecular characteristics and the underlying function of these WM cells have not been fully investigated. Highthroughput single-cell RNA sequencing (scRNA-seq) is a powerful approach for studying heterogeneous tissues and kinetics cellular processes [14,15]. Here, scRNA-seq analysis of BM mononuclear cells (BMNCs) from five newly diagnosed WM patients (NDWMs) and six healthy donors (HDs) were studied, and the heterogeneity of WM cells and non-malignant cells in the BM microenvironment was investigated.…”

Unlocking the potential of T‐cell metabolism reprogramming: Advancing single‐cell approaches for precision immunotherapy in tumour immunity

“…Trms constitute a Tm population that enters infected tissues during the effector phase of the immune response, ceasing direct involvement in the immune response within the circulatory system but counteracting renewed antigenic attack on local tissue 29 . A study of the aberrant metabolic microenvironment in the context of multiple myeloma revealed that CD69+STMN1+CD62L–CD8+ Trm cell‐related TCA cycle activity and amino acid metabolism were impaired, whereas glycolysis and FAO were enhanced, 91 corroborating the pivotal effect of FAO on immune memory mediated by Trms within the TME. More critically, in addition to providing energy support, fatty acid metabolism ensures maintenance of the nicotinamide adenine dinucleotide phosphate(NADPH) and ATP levels in Trms to safeguard them against reactive oxygen species (ROS) peroxidation 92 .…”

“…PIM kinase, a member of the serine/threonine kinase family, controls the phosphorylation of various proteins involved in cellular metabolism and survival and is closely associated with mTORC1 signalling activity to influence CD8+ T‐cell memory state formation 170 . The pan inhibitor of the PIM kinase AZD1208 inhibits mTOR signalling activity, preventing ROS interference with CD8+ Teff mitochondrial metabolism and restoring amino acid transport, thereby increasing CD8+ T‐cell toxicity and promoting Tm proliferation and persistence 91 . In addition, metformin phosphorylates AMPK to downregulate mTORC1 and induce the glycolysis‐dependent conversion of CD8+ T cells to FAO, contributing to enhanced acquisition of a memory phenotype and prolonged cell survival 155,149 .…”

The Interaction between Gut Microbiota and Host Amino Acids Metabolism in Multiple Myeloma

“…Another study assessed serine synthesis on MM progression, demonstrating that the increase of serine synthesis was related to the proliferation of MM cells, and higher expression of the related gene PHGDH was associated with a poor prognosis of MM [ 50 ]. Furthermore, abnormal amino acid metabolism promoted MM progression through the immunosuppressive microenvironment [ 51 ].…”