IFNγ Acts on Endothelial Cells to Promote Tumor Regression

IFNγ can act directly on cancer cells to inhibit tumor growth or act on the tumor stroma to promote rejection of established tumors, but it is not clear which stromal cells respond to IFNγ to facilitate tumor rejection. Using a mouse tumor model with inducible IFNγ in fibrosarcoma cells, Kammertoens and colleagues found that IFNγ induction promoted tumor regression mediated by the tumor stroma, not the cancer cells. Specifically, endothelial cells responded to IFNγ and were both necessary and sufficient for tumor regression, whereas the response of hematopoietic cells, including T cells and fibroblasts, to IFNγ was not sufficient to induce tumor regression. Further, IFNγ induction in endothelial cells induced necrosis and promoted the loss of endothelial cells. Mechanistically, IFNγ facilitated a vascular regression that arrested blood flow and promoted tumor ischemia to facilitate tumor regression. This is in contrast to TNF, which caused tumor blood vessels to burst. The controlled blood vessel regression induced by IFNγ is characteristic of nonapoptotic physiologic blood vessel regression that occurs in development, wound healing, and pregnancy-induced uterine artery remodeling, and distinct from hemorrhagic necrosis. Consistent with these findings, gene expression analysis revealed that IFNγ regulated genes associated with immune regulation and migration in endothelial cells including CXCL10 and CXCL11. Taken together, these findings demonstrate that IFNγ promotes tumor regression through effects on the tumor endothelial cells and provide insight into the mechanisms by which solid tumors are rejected, which may potentially guide improved adoptive T-cell therapy.

Kammertoens T, Friese C, Arina A, Idel C, Briesemeister D, Rothe M, et al. Tumour ischaemia by interferon-γ resembles physiological blood vessel regression. Nature 2017;545:98–102.