BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia
Infections represent a cause of morbidity and mortality in patients affected by chronic lymphocytic leukemia (CLL). Introduction of new drugs in CLL clinical practice has showed impressive efficacy, in particular those targeting BTK. Among the consistent clinical data, an increasing number of report...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.02158/full |
| _version_ | 1818212344083251200 |
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| author | Stefania Fiorcari Rossana Maffei Rossana Maffei Daniela Vallerini Lydia Scarfò Patrizia Barozzi Monica Maccaferri Leonardo Potenza Paolo Ghia Mario Luppi Roberto Marasca |
| author_facet | Stefania Fiorcari Rossana Maffei Rossana Maffei Daniela Vallerini Lydia Scarfò Patrizia Barozzi Monica Maccaferri Leonardo Potenza Paolo Ghia Mario Luppi Roberto Marasca |
| author_sort | Stefania Fiorcari |
| collection | DOAJ |
| description | Infections represent a cause of morbidity and mortality in patients affected by chronic lymphocytic leukemia (CLL). Introduction of new drugs in CLL clinical practice has showed impressive efficacy, in particular those targeting BTK. Among the consistent clinical data, an increasing number of reports describing the occurrence of unexpected opportunistic fungal infections has been reported during treatment with ibrutinib in the first 6 months of treatment. The reason underlying manifestations of invasive fungal infections in patients treated with ibrutinib is still under investigation. Our study aimed to understand the impact of BTK inhibition on immune response to fungal infection mediated by macrophages and CD14+ monocytic population obtained from CLL patients. Exposure to ibrutinib and acalabrutinib reduced signaling pathways activated by Aspergillus fumigatus determining an exacerbation of an immunosuppressive signature, a reduction of phagocytosis and a significant deficit in the secretion of inflammatory cytokines either in macrophages and monocytes isolated from CLL patients and healthy donors. These effects lead to a failure in completely counteracting conidia germination. In addition we investigated the biological effects of ibrutinib on monocyte counterpart in patients who were undergoing therapy. A significant impairment in cytokine secretion and a deficit of phagocytosis in circulating monocytes were detected after 3 months of treatment. Thus, our results uncover modifications in the innate response in CLL patients induced by ibrutinib that may impair the immunological response to fungal infection.KEYPOINTS•BTK inhibition affects a productive immune response of CLL-associated macrophages (NLC) during Aspergillus fumigatus infection.•Reduction of TNF-α secretion and phagocytosis are detected in monocytes isolated from CLL patients during ibrutinib therapy. |
| first_indexed | 2024-12-12T05:46:54Z |
| format | Article |
| id | doaj.art-372beb7d32184ca1a2059eb8678872fe |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T05:46:54Z |
| publishDate | 2020-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-372beb7d32184ca1a2059eb8678872fe2022-12-22T00:35:46ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-08-011110.3389/fimmu.2020.02158549796BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic LeukemiaStefania Fiorcari0Rossana Maffei1Rossana Maffei2Daniela Vallerini3Lydia Scarfò4Patrizia Barozzi5Monica Maccaferri6Leonardo Potenza7Paolo Ghia8Mario Luppi9Roberto Marasca10Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, ItalyHematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, ItalyHematology Unit, Department of Oncology and Hematology, A.O.U of Modena, Policlinico, Modena, ItalyHematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, ItalyUniversità Vita-Salute San Raffaele and IRCCS Istituto Scientifico San Raffaele, Milan, ItalyHematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, ItalyHematology Unit, Department of Oncology and Hematology, A.O.U of Modena, Policlinico, Modena, ItalyHematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, ItalyUniversità Vita-Salute San Raffaele and IRCCS Istituto Scientifico San Raffaele, Milan, ItalyHematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, ItalyHematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, ItalyInfections represent a cause of morbidity and mortality in patients affected by chronic lymphocytic leukemia (CLL). Introduction of new drugs in CLL clinical practice has showed impressive efficacy, in particular those targeting BTK. Among the consistent clinical data, an increasing number of reports describing the occurrence of unexpected opportunistic fungal infections has been reported during treatment with ibrutinib in the first 6 months of treatment. The reason underlying manifestations of invasive fungal infections in patients treated with ibrutinib is still under investigation. Our study aimed to understand the impact of BTK inhibition on immune response to fungal infection mediated by macrophages and CD14+ monocytic population obtained from CLL patients. Exposure to ibrutinib and acalabrutinib reduced signaling pathways activated by Aspergillus fumigatus determining an exacerbation of an immunosuppressive signature, a reduction of phagocytosis and a significant deficit in the secretion of inflammatory cytokines either in macrophages and monocytes isolated from CLL patients and healthy donors. These effects lead to a failure in completely counteracting conidia germination. In addition we investigated the biological effects of ibrutinib on monocyte counterpart in patients who were undergoing therapy. A significant impairment in cytokine secretion and a deficit of phagocytosis in circulating monocytes were detected after 3 months of treatment. Thus, our results uncover modifications in the innate response in CLL patients induced by ibrutinib that may impair the immunological response to fungal infection.KEYPOINTS•BTK inhibition affects a productive immune response of CLL-associated macrophages (NLC) during Aspergillus fumigatus infection.•Reduction of TNF-α secretion and phagocytosis are detected in monocytes isolated from CLL patients during ibrutinib therapy.https://www.frontiersin.org/article/10.3389/fimmu.2020.02158/fullchronic lymphocytic leibrutinibmacrophagesfungal infectionimmunomodulation |
| spellingShingle | Stefania Fiorcari Rossana Maffei Rossana Maffei Daniela Vallerini Lydia Scarfò Patrizia Barozzi Monica Maccaferri Leonardo Potenza Paolo Ghia Mario Luppi Roberto Marasca BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia Frontiers in Immunology chronic lymphocytic le ibrutinib macrophages fungal infection immunomodulation |
| title | BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia |
| title_full | BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia |
| title_fullStr | BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia |
| title_full_unstemmed | BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia |
| title_short | BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia |
| title_sort | btk inhibition impairs the innate response against fungal infection in patients with chronic lymphocytic leukemia |
| topic | chronic lymphocytic le ibrutinib macrophages fungal infection immunomodulation |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.02158/full |
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