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Inhibition of platelet GPVI induces intratumor hemorrhage and increases efficacy of chemotherapy in mice

Julia Volz, Elmina Mammadova-Bach, Jesus Gil-Pulido, Rajender Nandigama, Katharina Remer, Lydia Sorokin, Alma Zernecke, Scott I Abrams, Süleyman Ergün, Erik Henke and Bernhard Nieswandt

Key Points

  • Platelet GPVI is a key regulator of vascular integrity in growing tumors.

  • Inhibition of platelet GPVI induces tumor hemorrhage and increases efficacy of chemotherapeutics in mice.

Abstract

Maintenance of tumor vasculature integrity is indispensable for tumor growth and thus affects tumor progression. Previous studies have identified platelets as major regulators of tumor vascular integrity as their depletion selectively rendered tumor vessels highly permeable and caused massive intratumoral hemorrhage. While these results established platelets as potential targets for anti-tumor therapy, their depletion is not a treatment option due to their essential role for hemostasis. Thus, a detailed understanding of how platelets safeguard vascular integrity in tumors is urgently demanded. Here, we show for the first time that functional inhibition of glycoprotein (GP) VI on the platelet surface with an antibody (JAQ1) F(ab)2 fragment rapidly induces tumor hemorrhage and diminishes tumor growth similar to complete platelet depletion, while not inducing systemic bleeding complications. Both, the intra-tumor bleeding and tumor growth arrest could be reverted by depletion of Ly6G+ cells confirming them to be responsible for the induction of bleeding and necrosis within the tumor. In addition, JAQ1-F(ab)2-mediated GPVI inhibition increased intra-tumoral accumulation of co-administered chemotherapeutic agents, such as doxil and paclitaxel, thereby resulting in a profound anti-tumor effect. In summary, our findings identify platelet GPVI as a key regulator of vascular integrity specifically in growing tumors and could serve as a basis for the development of anti-tumor strategies based on the interference with platelet function.

  • Submitted September 25, 2018.
  • Revision received March 20, 2019.
  • Accepted April 2, 2019.