Modulating Tumor Immunity by Targeting Tumor Fibrotic Stroma and Angiogenic Vessels for Lung Cancer Treatment.

Simple Summary: Yuan et al. present a strategy to modulate tumor immunity by simultaneously depleting CAFs and tumor angiogenic vessels using a rationally designed protein that induces integrin α_vβ₃-expressing cell apoptosis. The study offers a unique opportunity for the enhancement of cancer immunotherapies, especially for patients with a tumor of dense stroma and high angiogenesis. Fibrotic stroma and angiogenic tumor vessels play an important role in modulating tumor immunity. We previously reported a rationally designed protein (ProAgio) that targets integrin α_vβ₃ at a novel site. ProAgio induces the apoptosis of cells that express high levels of the integrin. Both activated cancer-associated fibroblasts (CAFs) and angiogenic endothelial cells (aECs) in tumors express high levels of integrin α_vβ₃. ProAgio simultaneously and specifically induces apoptosis in CAFs and aECs in tumors. We provide evidence here that the depletion of CAFs and the elimination of leaky tumor angiogenic vessels by ProAgio alter tumor immunity. ProAgio reduces CD₄⁺ Treg and Myeloid-derived suppressor cells (MDSCs), increases CD₈⁺ T-cells, and increases the M1/M2 macrophage ratio in the tumor. The depletion of dense fibrotic stroma (CAFs) by ProAgio decreases the Programmed Death Ligand 1 (PDL-1) levels in the stroma areas surrounding the tumors, and thus strongly increases the delivery of anti-PDL-1 antibody to the target cancer cells. The impact of ProAgio on tumor immunity provides strong synergistical effects of checkpoint inhibitors on lung cancer treatment. [ABSTRACT FROM AUTHOR]