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

Resistance towards anti-angiogenic therapy (AAT) still represents a substantial clinical challenge. We report here that tumor-infiltrating mast cells (MC) are powerful mediators decreasing efficacy of AAT in mice and cancer patients. They act in a cell-extrinsic manner by secreting granzyme B, which liberates pro-angiogenic mediators from the extracellular matrix. In addition, MC also diminish efficacy of anti-angiogenic agents in a cell-autonomous way, which can be blocked by the mast cell degranulation inhibitor cromolyn. Our findings are relevant in humans because patients harboring higher numbers of MC in their tumors have an inferior outcome after anti-angiogenic treatment in the Gepar Quinto randomized Phase 3 clinical trial. Thus, MC-targeting might represent a novel promising approach to increase efficacy of AAT. Overall design: Panc02 cells were injected subcutanously into the flanks of C57BL/6J mice. After reaching a tumor volume of 100 mm3, mice were randomized into treatment and control group. The treatment group received 40 mg/kg of the anti-angiogenic anti-VEGFR2 antibody DC101 whereas the other group received a placebo. Mast cells from the peritoneum of tumor bearing mice were isolated by lavage. Mast cells from cell suspensions of both compartments were purified by FACS-sorting staining for DAPI, CD45, CD11b, CD117, and FceRI.