A druggable chromatin vulnerability in suppressive neutrophils restores antitumor immunity
Many cancers evade immunity by converting neutrophils into polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), but the chromatin mechanisms that maintain this pathological state remain unclear. Here we show that tumor-induced suppressive neutrophils depend on mSWI/SNF chromatin remodeling. Two orally bioavailable mSWI/SNF ATPase antagonists, a degrader and a catalytic inhibitor,…
Cancer cells can bypass immunity by transforming neutrophils into myeloid-derived suppressor cells (PMN-MDSCs). However, the chromatin mechanisms behind this suppression are not well understood. Researchers have discovered that mSWI/SNF chromatin remodeling plays a crucial role in maintaining these pathological neutrophils. They found that two orally active mSWI/SNF ATPase antagonists, a degrader and a catalytic inhibitor, can restore antitumor immunity in various cancer models, even those resistant to PD-1 blockade and to checkpoint therapy.
These treatments quickly eliminated intratumoral PMN-MDSCs, revived functional CD8+ T cells, and blocked the expansion and suppressive effects of PMN-MDSCs in both mouse and human samples. Moreover, mSWI/SNF antagonism altered chromatin accessibility and reduced PU.1/C/EBPβ occupancy at regulatory elements that sustain PMN-MDSC identity.
Therefore, this chromatin vulnerability in suppressive neutrophils may be targeted with drugs to enhance cancer immunity.
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