TNFR2 upregulation-caused loss of cell polarity prevents differentiation of myeloid-derived suppressor cells with ageing

Differentiation blockage can cause expansion of myeloid-derived suppressor cells (MDSCs) with ageing. Cell polarity loss (apolarity) in old stem or progenitor cells prevents their differentiation; but whether and how cell polarity is lost in old MDSCs, subsequently affecting their mature differentiation remains elusive. Here, we show that TNFR2 upregulation in old MDSCs triggers JNK over-activation, resulting in apolarity, differentiation blockage, and expansion of MDSCs with ageing. We find that TNFR2 expression in MDSCs can be induced by pro-inflammatory factors of senescence-associated secretory phenotype (SASP) and Tnfr2 deficiency in old mice significantly attenuates MDSCs’ differentiation blockage. Elevating TNFR2 expression in young MDSCs can induce apolarity and impair their differentiation; whereas suppressing JNK activity in old MDSCs can partially reverse their polarity and restore their differentiation capability. Therefore, TNFR2 aberrant upregulation represents a general mechanism by which extrinsic SASP signals dysregulate intrinsic cell polarity behaviors to arrest MDSCs’ mature differentiation during ageing.