Procoagulant platelets promote immune evasion in triple-negative breast cancer
Johanna B. Schaubaecher, Bojan Smiljanov, Florian Haring, Katja Steiger, Zhengquan Wu, Anais Ugurluoglu, Joshua Luft, Simone Ballke, Shaan Mahameed, Vera Schneewind, Jonas Hildinger, Martin Canis, Laura Mittmann, Constanze Braun, Gabriele Zuchtriegel, Rainer Kaiser, Leo Nicolai, Matthias Mack, Wilko Weichert, Kirsten Lauber, Bernd Uhl, Christoph A. Reichel
Abstract
ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive tumor entity in which immune checkpoint (IC) molecules are primarily synthesized in the tumor environment. Here, we report that procoagulant platelets bear large amounts of such immunomodulatory factors and that the presence of these cellular blood components in TNBC relates to protumorigenic immune-cell activity and impaired survival. Mechanistically, tumor-released nucleic acids attract platelets to the aberrant tumor microvasculature, where they undergo procoagulant activation, thus delivering specific stimulatory and inhibitory IC molecules. This concomitantly promotes protumorigenic myeloid leukocyte responses and compromises antitumorigenic lymphocyte activity, ultimately supporting tumor growth. Interference with platelet-leukocyte interactions prevented immune cell misguidance and suppressed tumor progression, nearly as effective as systemic IC inhibition. Hence, our data uncover a self-sustaining mechanism of TNBC by using platelets to misdirect immune-cell responses. Targeting this irregular multicellular interplay may represent a novel immunotherapeutic strategy for TNBC without the adverse effects of systemic IC inhibition.