Tumor-targeted TNFα stabilizes tumor vessels and enhances active immunotherapy

Solid tumors are intrinsically resistant to immune rejection. Abnormal tumor vasculature can act as a barrier for immune cell migration into tumors. We tested whether targeting IFN gamma and/or TNF alpha into pancreatic neuroendocrine tumors can alleviate immune suppression. We found that intratumoral IFN gamma causes rapid vessel loss, which does not support anti-tumor immunity. In contrast, low-dose TNF alpha enhances T-cell infiltration and overall survival, an effect that is exclusively mediated by CD8(+) effector cells. Intriguingly, lymphocyte influx does not correlate with increased vessel leakiness. Instead, low-dose TNF alpha stabilizes the vascular network and improves vessel perfusion. Inflammatory vessel remodeling is, at least in part, mediated by tumor-resident macrophages that are reprogrammed to secrete immune and angiogenic modulators. Moreover, inflammatory vessel remodeling with low-dose TNF alpha substantially improves antitumor vaccination or adoptive T-cell therapy. Thus, low-dose TNF alpha promotes both vessel remodeling and antitumor immune responses and acts as a potent adjuvant for active immunotherapy.