Metabolic Reprogramming Induces Immune Cell Dysfunction in the Tumor Microenvironment of Multiple Myeloma

Abstract

Tumor cells rewire metabolism to meet their increased nutritional demands, allowing the maintenance of tumor survival, proliferation, and expansion. Enhancement of glycolysis and glutaminolysis is identified in most, if not all cancers, including multiple myeloma (MM), which interacts with a hypoxic, acidic, and nutritionally deficient tumor microenvironment (TME). In this review, we discuss the metabolic changes including generation, depletion or accumulation of metabolites and signaling pathways, as well as their relationship with the TME in MM cells. Moreover, we describe the crosstalk among metabolism, TME, and changing function of immune cells during cancer progression. The overlapping metabolic phenotype between MM and immune cells is discussed. In this sense, targeting metabolism of MM cells is a promising therapeutic approach. We propose that it is important to define the metabolic signatures that may regulate the function of immune cells in TME in order to improve the response to immunotherapy.

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

“…Cancer cells, including MM cells, often shift the focus of their metabolic processes toward anaerobic cycles that produce lactate [ 91 , 92 , 93 , 94 , 95 , 96 ]. Lactate has even been shown to be preferred over glucose as an energy source by cancer cells in a well-oxygenated environment [ 91 , 92 , 93 , 94 ]. Usually, this would make the tumor cells less energetically efficient by adding more steps to the cellular respiration process.…”

“…This lactate shuttle pathway from oxygen-poor regions to oxygen-rich regions provides the oxygenated MM cells with an abundance of energy from lactate ( Figure 1 B). MM cell-derived lactate promotes the development of immunosuppressive Tregs and MDSCs [ 91 ]. Macrophages can sense lactate secreted from tumor cells and respond with immunosuppressive activity [ 92 , 93 , 94 ].…”

“…It is noteworthy that thiamine and magnesium sulphate that are ingredients of the anti-inflammatory, anti-oxidant investigational drug product RJX [ 81 ], which is being developed as a treatment platform against CRS, have been shown to facilitate lactate clearance in patients with sepsis. Likewise, targeting metabolic pathways that play a role in the development of a hypoxic TME in MM may provide the basis for innovative strategies with clinical impact potential [ 91 ].…”

The Emerging Role of Pyruvate Kinase M2 in Regulating Glutaminolysis via c-Myc

“…Besides tumor cells, metabolic reprogramming of glutaminolysis is observed in multiple cell types such as immune cells [38][39][40]. The role of dimer PKM2 in regulation of glutaminolysis in non-cancer cell types merits further investigations.…”

The role of bone marrow microenvironment in the progression of multiple myeloma from monoclonal gammopathy of undetermined significance

“…Клетки ММ влияют на макрофаги через выделение цитокинов, а накопленная в результате гликолиза мо лочная кислота может участвовать в эпигенетических изменениях в ядре макрофагов, что способствует их трансформации в опухолеассоциированные макро фаги (TAM) [25]. Они высвобождают IL6 и IL10, способствуют неоваскуляризации путем васкулогенной мимикрии и опосредованно через VEGF, IL8, фактор роста фибробластов 2 (FGF2), металлопротеиназы (MMPs), циклооксигеназу 2 (COX2) и колониестиму лирующий фактор 1 (CSF1) [24].…”