TNF-a Is a Potent Stimulator of Tc9-Cell Differentiation

Tumor-specific Tc9 cells exhibit an excellent antitumor potential in tumor immunotherapy. Identification of factors that contribute to Tc9-cell differentiation may have important clinical significance. In this study, we found that tumor necrosis factor (TNF)-α promotes Tc9 differentiation in vitro, and the TNF-α-induced Tc9 cells display enhanced cell survival and cell proliferation. More importantly, the TNF-α-induced tumor-specific Tc9 cells have increased antitumor capabilities in vivo. TNF-α activates its downstream signaling through 2 cell surface receptors, TNFR1 and TNFR2. In this study, we found that TNF-α promotes Tc9-cell differentiation through TNFR2, but not TNFR1. Furthermore, we found that TNF-α-TNFR2 activates STAT5 and nuclear factor-κB signaling during Tc9-cell differentiation. Blocking STAT5 or nuclear factor-κB by their specific inhibitors partially abrogates TNF-α-induced promotion of Tc9-cell differentiation. Thus, our study demonstrated TNF-α as a potent stimulator of Tc9-cell differentiation and may have important clinical implications.