Adrenergic signaling activates the tumor immune microenvironment in Multiple Myeloma

Research output: Unpublished contribution to conferencePoster

Abstract

Objectives
Adrenergic signaling stimulated by cortisol, norepinephrine and epinephrine controls a variety of physiological processes, including the immune system response. Preclinical studies have demonstrated that adrenergic signaling promotes tumor progression and negatively affects anti-tumor immune responses in solid tumor models. However, in the context of multiple myeloma (MM), little is known about the pro- and/or anti-tumoral role of adrenergic signaling in the bone marrow (BM) microenvironment. Therefore, in this study, we examined the impact of chronic stress on various immune cell populations and tumor load in MM-bearing mice. To recapitulate chronic stress, MM-bearing mice were exposed to restrained stress, which is a widely used model to mimic human depression and stress phenotypes. Effects on the immunological environment and tumor load were evaluated at distinct stages of disease progression.

Methods
To evaluate adrenergic receptor expression in the human and murine BM, we used the Heidelberg-Montpellier patient cohort and single-cell RNA sequencing data of the 5T33MM model. The chronic restraint stress protocol was used to stimulate adrenergic signaling in vivo (Frick et al., 2009). Naïve and 5T33MM-bearing C57BL/KaLwRij mice were daily (6h) subjected to restraint stress starting 7 days prior to tumor inoculation. Mice were sacrificed at different time points, 7 days post-tumor inoculation (DPI), 14-DPI and 20-DPI (~ end-stage). Immune cell populations in the BM and spleen were evaluated using multi-parameter flow cytometry.

Results
Among the β-adrenergic receptors (βAR), β2AR was heterogeneously expressed by B cells, T cells and myeloid cells in the BM of newly diagnosed MM patients and MM-bearing mice. Using the 5T33MM model, we found that daily restraint stress resulted in a significant reduction of tumor cells in the BM at end-stage of disease (20-DPI), while no anti-tumor effect could be observed for the spleen. At 7-DPI, we observed that stress induced neutrophilia (44.4% vs 57.8% within the CD45+ population) in the BM, and a same trend could be observed at later stages of disease progression. No significant differences were observed in other myeloid cell subsets (eosinophils, macrophages and monocytes). Chronic stress induced lymphocytosis in the spleen of MM-bearing mice with increased CD8+ T cells, NK and NKT cells (respectively 9.2% vs 11.9%; 2.3% vs 3.1% and 0.6% vs 1.0% within the CD45+ population at 14-DPI). In the splenic compartment, we also found increased IFN-y expression within the immune cell population, which was particularly expressed by the NK cells. Disease progression significantly reduced the percentage of B cells in the BM of MM-bearing mice, which was further decreased by chronic stress conditions (26.2% vs 12.5% at 14-DPI). Similar results on neutrophils, T cells, NK cells and B cells were observed in naïve mice exposed to chronic stress for 7-28 days.

Conclusion
Our findings unexpectedly demonstrate that stimulation of adrenergic signaling by chronic stress shifts the tumor microenvironment in MM towards an immune activated profile. This notion suggests that isoprenaline, a βAR-agonist, might increase the immunological response in MM and potentially improves the effects of current immunotherapeutic approaches. Novel in vivo experiments evaluating the impact of isoprenaline as single agent and in combination therapy will be conducted to validate this hypothesis.
Original languageEnglish
Publication statusUnpublished - 1 Feb 2024
Event39th General Annual Meeting of the BHS -
Duration: 2 Feb 20243 Feb 2024

Conference

Conference39th General Annual Meeting of the BHS
Period2/02/243/02/24

Keywords

  • adrenergic signaling
  • Multiple Myeloma
  • chronic stress
  • tumor immunology

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