Targeting dysregulated myeloid leukocyte-driven thrombopoiesis in triple negative breast cancer

• Applicant: Professor Dr. Christoph Reichel
• Subject Area: Gynaecology and Obstetrics ; Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545435037

Mammary malignancies represent the most common oncological disorder in women worldwide and one of the most frequent solid cancer entities overall. Thereof, triple-negative breast cancer (TNBC) accounts for 10 - 20 % of the cases. These heterogenous tumors do not express the therapeutically targetable receptors for estrogen, progesterone, or human epidermal growth factor receptor 2 and belong to the most aggressive breast cancer types. For a long time, therapeutic options in TNBC were limited to surgical, radiotherapeutic, as well as anthracycline- and/or taxane-based chemotherapies. Novel targeted therapies including inhibitors of the programmed cell death ligand-1 - programmed death protein-1 (PD-L1 - PD-1) immune checkpoint, however, brought progress to the treatment of this tumor entity - albeit the benefit of these drugs in TNBC varies widely between affected individuals. Recently, our group was able to demonstrate that highly-reactive platelets accumulate in the TNBC microvasculature to misguide immune cell responses by the delivery of immune checkpoint molecules such as PD-L1 (unpublished). Own preliminary data further propose a model, in which the tumor-released cytokine thrombopoietin stimulates excessive interactions of neutrophils and classical monocytes with bone marrow megakaryocytes (MK) in TNBC, thus promoting the production of immature (reticulated) platelets into the bloodstream to foster disease progression. The mechanisms underlying these pathological processes, however, are still unclear. The objectives of the present proposal therefore are i) to decipher the signals attracting neutrophils and classical monocytes to bone marrow MK in TNBC, ii) to elucidate the mechanisms underlying the neutrophil- and classical monocyte-dependent formation of young, reticulated platelets in TNBC, and iii) to characterize tumorigenic properties of young, reticulated platelets induced by these events. The results of these studies will contribute to a more comprehensive understanding of the complex interplay between the immune system and haemostasis in cancer and might provide the basis for innovative immunotherapeutic concepts in the treatment of TNBC.

• DFG Programme: Research Grants