Pathological angiogenesis is a hallmark of cancer and therapeutic target. Vascular-endothelial growth factor-A (VEGFA) and angiopoietin-2 (ANGPT2) sustain tumor angiogenesis and limit anti-tumor immunity. Here we show that combined ANGPT2 and VEGFA blockade by a bi-specific antibody (A2V) provided synergistic anti-tumoral benefits in transgenic and transplant tumor models, including metastatic breast cancer, pancreatic neuroendocrine tumor, and melanoma. Mechanistically, A2V promoted tumor vascular regression, necrosis, and antigen presentation by intra-tumoral phagocytes. A2V also normalized the remaining blood vessels and facilitated the extravasation and perivascular accumulation of activated, interferon- (IFN)-expressing CD8+ cytotoxic T lymphocytes (CTLs). While the anti-tumoral activity of A2V was partly CTL-dependent, CTLs concurrently upregulated the immune checkpoint ligand PDL1 in the vascular endothelial cells. IFN neutralization blunted this adaptive response, and PD1 blockade improved tumor control by A2V in different cancer models. These findings position CTLs as key effectors of anti-angiogenic therapy and support the rationale for co-targeting angiogenesis and immune checkpoints in cancer therapy. SOURCE: Chia-Huey Ooi (chia-huey.ooi@roche.com) -  F. Hoffmann-La Roche Ltd.

Pluto Bioinformatics

GSE94920: Dual angiopoietin-2 and VEGFA inhibition elicits anti-tumor immunity that is enhanced by PD1 checkpoint blockade