Intratumoral TNFα improves immunotherapy

Abstract

Solid tumors are frequently resistant to immunotherapy. We demonstrated that low-dose tumor necrosis factorα (TNFα), when directly targeted to the tumor environment, exerts dual effects by improving vessel functionality and activating immune cells. This vascular remodeling in an inflammatory context enhances active immunotherapy and promotes tumor regression.

Figure 1. Intratumoral low-dose tumor necrosis factor α (TNFα-RGR, TNFα conjugated with vascular homing peptide, injected i.v.) increases tumor vessel stability and vascular perfusion. Remodeled vessels are highly activated and express VCAM, vascular cell adhesion molecule (VCAM). Tumor resident macrophages switch from a M2 to a M1 phenotype, express high levels of VCAM, monocyte chemotactic protein 1 (MCP1), interleukin 6 (IL-6), inducible nitric oxide synthetase (iNOS) and angiopoietin 2 (Ang2), and cluster around tumor vessels. Adoptively transferred antitumor T cells are unable to penetrate into untreated tumors, but infiltrate tumors after “pre-conditioning” with TNFα, which leads to tumor regression.