Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme B

Abstract

Resistance towards VEGF-centered anti-angiogenic therapy still represents a substantial clinical challenge. We report here that mast cells alter the proliferative and organizational state of endothelial cells which reduces the efficacy of anti-angiogenic therapy. Consequently, absence of mast cells sensitizes tumor vessels for anti-angiogenic therapy in different tumor models. Mechanistically, anti-angiogenic therapy only initially reduces tumor vessel proliferation, however, this treatment effect was abrogated over time as a result of mast cell-mediated restimulation of angiogenesis. We show that mast cells secrete increased amounts of granzyme b upon therapy, which mobilizes pro-angiogenic laminin- and vitronectin-bound FGF-1 and GM-CSF from the tumor matrix. In addition, mast cells also diminish efficacy of anti-angiogenic therapy by secretion of FGF-2. These pro-angiogenic factors act beside the targeted VEGFA–VEGFR2-axis and reinduce endothelial cell proliferation and angiogenesis despite the presence of anti-angiogenic therapy. Importantly, inhibition of mast cell degranulation with cromolyn is able to improve efficacy of anti-angiogenic therapy. Thus, concomitant mast cell-targeting might lead to improved efficacy of anti-angiogenic therapy.

Blockade of Myeloid-Derived Suppressor Cell Expansion with All-Trans Retinoic Acid Increases the Efficacy of Antiangiogenic Therapy

“…Next, we quantified the fraction of proliferating vessels after injection of BrdUrd. These analyses revealed an increase of BrdUrd þ vessels upon DC101 treatment compared with control treatment as previously described (27), whereas ATRA monotherapy had no effect (Fig. 3D).…”

Role of Mast Cells in Shaping the Tumor Microenvironment

“…Wroblewski et al showed that MCs release FGF-2 that acts on ECs and induces their proliferation and promotes angiogenesis. The combination of cromolyn to prevent MC degranulation along with anti-angiogenic therapy promoted the therapeutic efficacy [74]. The engagement of TLR2 on MC has shown to stimulate tumor growth, and blocking this pathway may be promising in designing of immunotherapeutic strategies.…”

Retinal Distribution and Extracellular Activity of Granzyme B: A Serine Protease That Degrades Retinal Pigment Epithelial Tight Junctions and Extracellular Matrix Proteins

“…Moreover, some patients on anti-VEGF drugs do not benefit (e.g., non-responders) and their vision continues to diminish. Insights into a mechanism underlying resistance observed in some AMD non-responders come from a recent article by Wroblewski et al that showed increased levels of GzmB from mast cells upon anti-VEGF treatment for cancer (tumor angiogenesis) (56). In Wroblewski et al, activity of extracellular GzmB was shown to liberate sequestered pro-angiogenic factors (from the tumor ECM) outside the VEGF-VEGFR2 axis.…”