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2017 ; 6
(1
): e1258503
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Identification of inhibitors of myeloid-derived suppressor cells activity through
phenotypic chemical screening
#MMPMID28197378
Schröder M
; Loos S
; Naumann SK
; Bachran C
; Krötschel M
; Umansky V
; Helming L
; Swee LK
Oncoimmunology
2017[]; 6
(1
): e1258503
PMID28197378
show ga
Tumors are infiltrated by cells of the immune system that interact through
complex regulatory networks. Although tumor-specific CD8(+) T cells can be found
in peripheral blood and tumor samples from cancer patients, their function is
inhibited by immunosuppressive cells such as regulatory T cells, tumor-associated
macrophages, and myeloid-derived suppressor cells (MDSC). Recent clinical
successes have demonstrated that alleviating immunosuppression and T cell
exhaustion translates into long-term clinical benefits. Although tremendous
progress has been achieved, tools that afford unbiased approaches and screenings
to uncover new potential inhibitors or gene targets are lacking. In this study,
we describe a system based on immortalized progenitors that allows
straightforward investigation of myeloid cells. We show that bone marrow
progenitors immortalized through the transduction of NUP98-HOXB4 transgene can be
differentiated into CD11b(+)Gr-1(+) MDSC that express Arginase-1 and PD-L1,
produce reactive oxygen and nitrogen species, and suppress T cell function in
vitro. To uncover chemical probes that interfere with MDSC biology, we performed
a chemical phenotypic screening and identified 3-deazaneplanocin A as a novel
modulator of MDSC functions. We characterized and compared the effect of
3-deazaneplanocin-A and all-trans retinoic acid, a well-known modulator of MDSC
activity, on the expression of effector molecules and immunosuppressive functions
of MDSC. Altogether, this proof-of-principle opens new possibilities for the
identification of drugs targeting myeloid cells with immunosuppressive
activities.