TNFR2 signaling promotes monocytic-MDSC differentiation and production of immunosuppressive mediators.

Myeloid-derived suppressor cells (MDSCs) differentiate and proliferate in the pathological context of cancer, suppress T-cell responses, and promote tumor progression and therapeutic resistance. These cells express high levels of TNF receptor type 2 (TNFR2), but the ligand TNF-α also activates TNFR1, masking TNFR2-specific function. We analyzed TNFR2 signaling using GM-CSF-induced MDSCs from TNFR2-knockout mice and scR2agoTNF-Fc, a TNFR2-selective agonist. Stimulation with scR2agoTNF-Fc maintained a highly suppressive monocytic subset. TNFR2 deficiency reduced MDSC-mediated T-cell suppression. TNFR2 activation also increased the expression of immunosuppressive effector molecules such as inducible nitric-oxide synthase and interleukin-10. These results indicate that TNFR2 is a promising therapeutic target for modulating the differentiation and immunosuppressive functions of MDSC subsets.