engLazarevic, JelenaWagner, WolfgangSchemionek-Reinders, MirleLiposomal dexamethasone combined with CD47 blockade is a promising strategy for overcoming multiple myeloma resistanceinfo:eu-repo/classification/ddc/570Multiple myeloma (MM) is a proliferative malignancy of plasma cells in the bone marrow. Despite advancements in treatment, MM remains incurable, with relapse being virtually inevitable after first-line therapy, ultimately contributing to poor patient prognosis. A major factor in the disease’s aggressiveness is the presence of a poorly characterized stem cell-like population, as well as the dynamic interactions between malignant cells and the tumor microenvironment (TME). Standard treatment regimens, including dexamethasone as part of multi-drug protocols, provide symptomatic relief but fail to achieve long-term remission and are often associated with significant side effects. Among the cellular components of the TME, macrophages have emerged as critical regulators of MM pathogenesis, progression, and resistance to therapy. The interplay between MM cells and macrophages is increasingly recognized as a driving force behind immune evasion and disease persistence. CD47, an immune checkpoint molecule that acts as a “don’t eat me” signal by binding to signal regulatory protein alpha (SIRPα) on macrophages, is consistently overexpressed on MM cells. This makes CD47 a promising therapeutic target to restore macrophage-mediated clearance of malignant cells. In this study, we addressed the limitations of conventional dexamethasone therapy—specifically its poor pharmacokinetics and non-specific tissue distribution—by employing a liposomal encapsulation strategy. Our data demonstrate that liposomal dexamethasone outperforms the free drug formulation in several preclinical settings. We observed that dexamethasone treatment led to an enrichment of the MM stem cell-like compartment, a population associated with therapy resistance, disease relapse, and invasiveness. Concurrently, we observed an upregulation of both pro-phagocytic, “eat me,” e.g. calreticulin (CALR) and anti-phagocytic, “don’t eat me,” e.g. CD47 signals. This dual modulation suggests that CD47 upregulation may serve as a resistance mechanism, enabling MM cells to evade immune-mediated clearance. Interestingly, the effects of dexamethasone on CD47 expression differed between MM subpopulations. While mature, CD138pos cells exhibited increased CD47 expression following treatment, CD138neg stem cell-like cells showed a relative downregulation. We hypothesize that this differential expression may sensitize the stem-like compartment to immune clearance, while CD47-overexpressing mature cells may provide a protective microenvironment. To enhance the targeting of both bulk and stem-like MM cells, and to disrupt immune checkpoint-mediated resistance, we evaluated anti-CD47 therapy alone and in combination with liposomal dexamethasone. While anti-CD47 monotherapy exerted a measurable anti-myeloma effect, the combination therapy demonstrated a more pronounced impact, particularly on the stem cell-like population. This combinatorial approach significantly enhanced macrophage-mediated phagocytosis in vitro. Additionally, dexamethasone treatment induced an anti-inflammatory macrophage phenotype, consistent with previous findings, potentially facilitating a more proactive macrophage role in malignant cell clearance when used alongside anti-CD47 therapy. In summary, our data support the benefit of combining anti-CD47 therapy with liposomal dexamethasone as a strategy to overcome drug resistance and immune evasion in multiple myeloma.Aachen : RWTH Aachen University 1 Online-Ressource : Illustrationen (2025). doi:10.18154/RWTH-2025-10304 = Dissertation, RWTH Aachen University, 2025info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionRWTH Aachen University2025info:eu-repo/semantics/openAccessDEhttps://publications.rwth-aachen.de/record/1022842https://publications.rwth-aachen.de/search?p=id:%22RWTH-2025-10304%22StudentsStudent Financial Aid ProvidersTeachersResearchersinfo:eu-repo/semantics/altIdentifier/doi/10.18154/RWTH-2025-10304