Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy

Significance Cancer immunotherapy demonstrates clinical efficacy in selected cancer types. Yet, as the majority of patients do not respond to the most effective immunotherapeutics, novel immunotherapy combinations are extensively investigated. There is increasing clinical interest in combining cancer immunotherapies with antiangiogenic agents, particularly VEGFA pathway inhibitors. Here we show that anti-CD40 immunotherapy increases CD8+ T cell infiltration in the tumor, yet tumor regression is achieved more robustly when anti-CD40 is combined with dual Ang2 and VEGFA blockade, but not VEGFA inhibition alone. Tumor regression was associated with proinflammatory skewing of the tumor microenvironment and intratumoral redistribution of CD8+ T cells. These data emphasize the rationale for blocking Ang2 as a vascular-modulatory strategy in combination with T cell-targeting immunotherapies. Cancer immunotherapies are increasingly combined with targeted therapies to improve therapeutic outcomes. We show that combination of agonistic anti-CD40 with antiangiogenic antibodies targeting 2 proangiogenic factors, vascular endothelial growth factor A (VEGFA) and angiopoietin 2 (Ang2/ANGPT2), induces pleiotropic immune mechanisms that facilitate tumor rejection in several tumor models. On the one hand, VEGFA/Ang2 blockade induced regression of the tumor microvasculature while decreasing the proportion of nonperfused vessels and reducing leakiness of the remaining vessels. On the other hand, both anti-VEGFA/Ang2 and anti-CD40 independently promoted proinflammatory macrophage skewing and increased dendritic cell activation in the tumor microenvironment, which were further amplified upon combination of the 2 treatments. Finally, combined therapy provoked brisk infiltration and intratumoral redistribution of cytotoxic CD8+ T cells in the tumors, which was mainly driven by Ang2 blockade. Overall, these nonredundant synergistic mechanisms endowed T cells with improved effector functions that were conducive to more efficient tumor control, underscoring the therapeutic potential of antiangiogenic immunotherapy in cancer.