Blocking angiopoietin-2 promotes vascular damage and growth inhibition in mouse tumors treated with small doses of radiation

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-06, Vol.80 (12), p.2639-2650
• Main Authors: Kallio, Pauliina, Jokinen, Elina, Högström, Jenny, Das, Suvendu, Heino, Sarika, Lähde, Marianne, Brodkin, Jefim, Korhonen, Emilia A, Alitalo, Kari
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-20-0497

Abnormal vasculature in tumors leads to poor tissue perfusion and cytostatic drug delivery. Although drugs inducing vascular normalization, e.g., angiopoietin-2 (Ang2)-blocking antibodies, have shown promising results in preclinical tumor models, clinical studies have so far shown only little efficacy. Since Ang2 is known to play a protective role in stressed endothelial cells, we tested here if Ang2 blocking could enhance radiation-induced tumor vascular damage. Tumor-bearing mice were treated with anti-Ang2 antibodies every three or four days starting three days before 3x2 Gy or 4x0.5 Gy whole-body or tumor-focused radiation. Combination treatment with anti-Ang2 and radiation improved tumor growth inhibition and extended the survival of mice with melanoma or colorectal tumors. Single-cell RNA sequencing revealed that Ang2 blocking rescued radiation-induced decreases in T cells and cells of the monocyte/macrophage lineage. In addition, anti-Ang2 enhanced radiation-induced apoptosis in cultured endothelial cells. In vivo, combination treatment decreased tumor vasculature and increased tumor necrosis in comparison with tumors treated with monotherapies. These results suggest that a combination of Ang2 blocking antibodies with radiation increases tumor growth inhibition and extends the survival of tumor-bearing mice.