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@PHDTHESIS{Lazarevic:1022842,
author = {Lazarevic, Jelena},
othercontributors = {Wagner, Wolfgang and Schemionek-Reinders, Mirle},
title = {{L}iposomal dexamethasone combined with {CD}47 blockade is
a promising strategy for overcoming multiple myeloma
resistance},
school = {RWTH Aachen University},
type = {Dissertation},
address = {Aachen},
publisher = {RWTH Aachen University},
reportid = {RWTH-2025-10304},
pages = {1 Online-Ressource : Illustrationen},
year = {2025},
note = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
University 2026; Dissertation, RWTH Aachen University, 2025},
abstract = {Multiple 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.},
cin = {811002-3 ; 924120 / 160000},
ddc = {570},
cid = {$I:(DE-82)811002-3_20140620$ / $I:(DE-82)160000_20140620$},
pnm = {GRK 2375 - GRK 2375: Tumor-Targeted Drug Delivery
(331065168)},
pid = {G:(GEPRIS)331065168},
typ = {PUB:(DE-HGF)11},
doi = {10.18154/RWTH-2025-10304},
url = {https://publications.rwth-aachen.de/record/1022842},
}
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