P-03.03 Granulopoiesis and thrombopoiesis aberrantly synergize in cancer to promote tumor progression

<h3>Background</h3> Myeloid cells acquire tumor-supporting properties in cancer. Clinical strategies targeting this pathological process, however, are not established since the underlying mechanisms remain ill-defined. This study aimed at investigating tumor-elicited effects on bone marrow thrombopoiesis and granulopoiesis, thus uncovering the occurence of an aberrant, pro-tumorigenic interplay of these fundamental biological processes in cancer. <h3>Materials and Methods</h3> <i>In vitro</i> assays and mass spectrometry-based proteomics along with advanced <i>in vivo</i>/<i>ex vivo</i> microscopy techniques were employed in mouse models of TNBC. Transcriptomic, flow cytometric, and immunohistochemical analyses were performed in human bone marrow, blood, and/or tumors in triple-negative breast cancer (TNBC) and other solid cancers to validate identified molecular targets. <h3>Results</h3> Bone marrow megakaryocytes adopt an anabolic-inflammatory state in TNBC, which attracts aged neutrophils having returned from the circulation. Subsequently, these neutrophils form extracellular traps, in which myeloperoxidase destabilizes megakaryocyte extensions (=proplatelets) through hypochlorous acid-dependent processes. This enables monocytes to shed proplatelets into the bloodstream, thus generating immature/reticulated platelets with highly immunomodulatory properties. Concomitantly, megakaryocyte interactions with neutrophils freshly produced by tumor-initiated granulopoiesis shift their phenotype pro-angiogenic, before these neutrophils leave the bone marrow. In the tumor, immature/reticulated platelets recruit pro-angiogenic neutrophils for aberrant vessel formation, collectively fueling malignant growth. Mechanistically, these events rely on excessive tumor-associated thrombopoietin production, which correlates with impaired survival in various solid cancers. <h3>Conclusions</h3> Our translational studies identify a self-supporting mechanism in solid malignancies that synergistically dysregulates bone marrow granulo- and thrombopoiesis. Interfering with this irregular interrelation of hemostasis and immune system might represent an innovative concept to counteract tumor progression in TNBC and other cancers. B. Smiljanov: None.