Tumor-targeted TNFα stabilizes tumor vessels and enhances active immunotherapy.

Abstract

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 IFNγ and/or TNFα into pancreatic neuroendocrine tumors can alleviate immune suppression. We found that intratumoral IFNγ causes rapid vessel loss, which does not support anti-tumor immunity. In contrast, low-dose TNFα 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 TNFα 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 TNFα substantially improves antitumor vaccination or adoptive T-cell therapy. Thus, low-dose TNFα promotes both vessel remodeling and antitumor immune responses and acts as a potent adjuvant for active immunotherapy.

DOI: 10.1073/pnas.1118296109
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@article{Johansson2012TumortargetedTS, title={Tumor-targeted TNFα stabilizes tumor vessels and enhances active immunotherapy.}, author={Anna H. Johansson and Juliana Hamzah and Christine J. Payne and Ruth Ganss}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2012}, volume={109 20}, pages={7841-6} }