Immunomodulatory Drugs Alter the Metabolism and the Extracellular Release of Soluble Mediators by Normal Monocytes

Abstract

Immunomodulatory drugs (IMiDs) are used in the treatment of hematological malignancies, especially multiple myeloma. IMiDs have direct anticancer effects but also indirect effects via cancer-supporting stromal cells. Monocytes are a stromal cell subset whose metabolism is modulated by the microenvironment, and they communicate with neighboring cells through extracellular release of soluble mediators. Toll-like receptor 4 (TLR4) is then a common regulator of monocyte metabolism and mediator release. Our aim was to investigate IMiD effects on these two monocyte functions. We compared effects of thalidomide, lenalidomide, and pomalidomide on in vitro cultured normal monocytes. Cells were cultured in medium alone or activated by lipopolysaccharide (LPS), a TLR4 agonist. Metabolism was analyzed by the Seahorse XF 96 cell analyzer. Mediator release was measured as culture supernatant levels. TLR4 was a regulator of both monocyte metabolism and mediator release. All three IMiDs altered monocyte metabolism especially when cells were cultured with LPS; this effect was strongest for lenalidomide that increased glycolysis. Monocytes showed a broad soluble mediator release profile. IMiDs decreased TLR4-induced mediator release; this effect was stronger for pomalidomide than for lenalidomide and especially thalidomide. To conclude, IMiDs can alter the metabolism and cell–cell communication of normal monocytes, and despite their common molecular target these effects differ among various IMiDs.

Combined C-Reactive Protein and Novel Inflammatory Parameters as a Predictor in Cancer—What Can We Learn from the Hematological Experience?

“…Furthermore, total monocyte levels normalize early after both allogeneic and autologous stem cell transplantation, but patients differ with regard to the early reconstitution of the three main monocyte subsets [ 129 , 130 ]. Experimental studies have shown that even closely related pharmacological agents can differ in their effects on normal monocyte functions [ 131 ], and futures studies therefore have to clarify whether functional differences of anticancer agents between patients reflect differences in circulating monocyte subset levels. In our opinion, characterization of circulating monocyte subsets should be further investigated as a possible prognostic biomarker in cancer patients, including patients receiving allogeneic stem cell transplantation and immunotherapy.…”

The Acute Phase Reaction and Its Prognostic Impact in Patients with Head and Neck Squamous Cell Carcinoma: Single Biomarkers Including C-Reactive Protein Versus Biomarker Profiles

“…These cytokine receptors thus have a partial overlap with regard to the downstream targets of their receptors. Finally, there may also be a coordinated release for several of these cytokines, e.g., the release of IL1/IL6/TNFα by monocytes activated in response to Toll-like receptor ligation, because such monocyte activation will induce a broad cytokine release response [ 70 ]. It is not known whether such a chemokine response will influence or modify the overall biological effects of acute phase reactions.…”

Cytokine Release Syndrome in the Immunotherapy of Hematological Malignancies: The Biology behind and Possible Clinical Consequences

“…Toll-like receptors (TLRs) and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway are potent activator of monocytes/macrophages [ 33 ]. In addition, previous studies have shown that TLRs activation is involved in the development of cytokine storm as a complication to various diseases [ 34 , 35 , 36 ].…”