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

Volz J, Mammadova-Bach E, Gil-Pulido J, Nandigama R, Remer K, Sorokin L, Zernecke A, Abrams SI, Erguen S, Henke E, Nieswandt B (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Blood American Society of Hematology

Book Volume: 133

Pages Range: 2696-2706

Journal Issue: 25

DOI: 10.1182/blood.2018877043

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 antitumor therapy, their depletion is not a treatment option due to their essential role in 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 VI (GPVI) 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. The intratumor bleeding and tumor growth arrest could be reverted by depletion of Ly6G1 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 intratumoral accumulation of coadministered chemotherapeutic agents, such as Doxil and paclitaxel, thereby resulting in a profound antitumor 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 antitumor strategies based on the interference with platelet function.

Involved external institutions

Universitätsklinikum Würzburg DE Germany (DE) Julius-Maximilians-Universität Würzburg DE Germany (DE) Westfälische Wilhelms-Universität (WWU) Münster DE Germany (DE) Roswell Park Cancer Institute US United States (USA) (US)

How to cite

APA:

Volz, J., Mammadova-Bach, E., Gil-Pulido, J., Nandigama, R., Remer, K., Sorokin, L.,... Nieswandt, B. (2019). Inhibition of platelet GPVI induces intratumor hemorrhage and increases efficacy of chemotherapy in mice. Blood, 133(25), 2696-2706. https://doi.org/10.1182/blood.2018877043

MLA:

Volz, Julia, et al. "Inhibition of platelet GPVI induces intratumor hemorrhage and increases efficacy of chemotherapy in mice." Blood 133.25 (2019): 2696-2706.

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