BTK Inhibitors Impair Platelet-Mediated Antifungal Activity

Cells

Rossella Manfredini¹  Enrico Tagliafico²  Giovanni Riva²  Tommaso Trenti²  Vincenzo Nasillo²  Patrizia Comoli³  Ivana Lagreca⁴  Roberto Marasca⁴  Rossana Maffei⁴  Mario Luppi⁴  Claudio Giacinto Atene⁴  Stefania Fiorcari⁴  Daniela Vallerini⁴  Leonardo Potenza⁴  Silvia Martinelli⁴  Fabio Forghieri⁴  Ilaria Castelli⁴  Monica Maccaferri⁴  Patrizia Barozzi⁴  Ambra Paolini⁴ 

[1] Centre for Regenerative Medicine “S. Ferrari”, University of Modena and Reggio Emilia, 41125 Modena, Italy;Diagnostic Hematology and Clinical Genomics, Department of Laboratory Medicine and Pathology, AUSL/AOU Modena, 41124 Modena, Italy;Pediatric Hematology/Oncology Unit and Cell Factory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, 27100 Pavia, Italy;Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, 41124 Modena, Italy;

关键词: BTK inhibitors;    platelets;    ibrutinib;    acalabrutinib;    CLL;    invasive fungal infections;   

DOI  :  10.3390/cells11061003

来源: DOAJ

【 摘 要 】

In recent years, the introduction of new drugs targeting Bruton’s tyrosine kinase (BTK) has allowed dramatic improvement in the prognosis of patients with chronic lymphocytic leukemia (CLL) and other B-cell neoplasms. Although these small molecules were initially considered less immunosuppressive than chemoimmunotherapy, an increasing number of reports have described the occurrence of unexpected opportunistic fungal infections, in particular invasive aspergillosis (IA). BTK represents a crucial molecule in several signaling pathways depending on different immune receptors. Based on a variety of specific off-target effects on innate immunity, namely on neutrophils, monocytes, pulmonary macrophages, and nurse-like cells, ibrutinib has been proposed as a new host factor for the definition of probable invasive pulmonary mold disease. The role of platelets in the control of fungal growth, through granule-dependent mechanisms, was described in vitro almost two decades ago and is, so far, neglected by experts in the field of clinical management of IA. In the present study, we confirm the antifungal role of platelets, and we show, for the first time, that the exposure to BTK inhibitors impairs several immune functions of platelets in response to Aspergillus fumigatus, i.e., the ability to adhere to conidia, activation (as indicated by reduced expression of P-selectin), and direct killing activity. In conclusion, our experimental data suggest that antiplatelet effects of BTK inhibitors may contribute to an increased risk for IA in CLL patients.

【 授权许可】

Unknown