TH2/TH1 Shift Under Ibrutinib Treatment in Chronic Lymphocytic Leukemia
Ibrutinib may revert the T-helper (Th)2 polarization observed in chronic lymphocytic leukemia (CLL) by targeting the IL-2-inducible kinase, that shows a significant homology with the Bruton tyrosine kinase. In the front-line GIMEMA LLC1114 trial (ibrutinib+rituximab for 6 months, followed by ibrutin...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-04-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.637186/full |
| _version_ | 1818426984662827008 |
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| author | Maria Cristina Puzzolo Ilaria Del Giudice Nadia Peragine Paola Mariglia Maria Stefania De Propris Luca Vincenzo Cappelli Livio Trentin Gianluigi Reda Antonio Cuneo Stefano Molica Alfonso Piciocchi Valentina Arena Francesca Romana Mauro Anna Guarini Robin Foà |
| author_facet | Maria Cristina Puzzolo Ilaria Del Giudice Nadia Peragine Paola Mariglia Maria Stefania De Propris Luca Vincenzo Cappelli Livio Trentin Gianluigi Reda Antonio Cuneo Stefano Molica Alfonso Piciocchi Valentina Arena Francesca Romana Mauro Anna Guarini Robin Foà |
| author_sort | Maria Cristina Puzzolo |
| collection | DOAJ |
| description | Ibrutinib may revert the T-helper (Th)2 polarization observed in chronic lymphocytic leukemia (CLL) by targeting the IL-2-inducible kinase, that shows a significant homology with the Bruton tyrosine kinase. In the front-line GIMEMA LLC1114 trial (ibrutinib+rituximab for 6 months, followed by ibrutinib maintenance), we investigated the modulation of T-cell cytokine production in 208 peripheral blood paired samples from 71 CLL patients: 71 samples prior to treatment (Day 0, D0) and at day +14 (D14; n=50), at month +8 (M8; 30), +12 (M12; 25), +18 (M18; 22) and +24 (M24; 10) of treatment. We documented a progressive decrease of CD3+CD4+IL-4+ T cells (Th2), that was significant at M8 and at M12 (p=0.019, p=0.002), a relative increase in the CD3+CD4+IFNγ+ T cells (Th1) and a decrease of CD3+CD4+IL-17+ (Th17) cells that was maintained up to M18 (M8 vs D0 p=0.003, M12 vs D0 p=0.003, M18 vs D0 p=0.004) of ibrutinib treatment. The Th2/Th1 ratio significantly decreased already after 14 days of treatment and was maintained thereafter (D14 vs D0 p=0.037, M8 vs D0 p=0.001, M12 vs D0 p=0.005, M18 vs D0 p=0.002). The Th2/Th1 modulation over time was significant only among patients with unmutated IGHV. The Th2/Th1 ratio below a cut-off of 0.088 at M8 was associated with the achievement of a complete response (CR) (p=0.016). Ibrutinib may shape the CLL T-cell profile, limiting Th2 activation and inducing a shift in the Th2/Th1 ratio. The association between the Th2/Th1 ratio decrease and the CR achievement suggests the in vivo generation of a potential host anti-tumor immune activation induced by ibrutinib. |
| first_indexed | 2024-12-14T14:38:31Z |
| format | Article |
| id | doaj.art-cd628b4fa6a448cf8cad11aced4c9099 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-14T14:38:31Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-cd628b4fa6a448cf8cad11aced4c90992022-12-21T22:57:29ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-04-011110.3389/fonc.2021.637186637186TH2/TH1 Shift Under Ibrutinib Treatment in Chronic Lymphocytic LeukemiaMaria Cristina Puzzolo0Ilaria Del Giudice1Nadia Peragine2Paola Mariglia3Maria Stefania De Propris4Luca Vincenzo Cappelli5Livio Trentin6Gianluigi Reda7Antonio Cuneo8Stefano Molica9Alfonso Piciocchi10Valentina Arena11Francesca Romana Mauro12Anna Guarini13Robin Foà14Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, ItalyHematology, Department of Translational and Precision Medicine, Sapienza University, Rome, ItalyHematology, Department of Translational and Precision Medicine, Sapienza University, Rome, ItalyHematology, Department of Translational and Precision Medicine, Sapienza University, Rome, ItalyHematology, Department of Translational and Precision Medicine, Sapienza University, Rome, ItalyHematology, Department of Translational and Precision Medicine, Sapienza University, Rome, ItalyHematology Unit, University of Padua, Padua, ItalyHematology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, ItalyHematology Section, Department of Medical Science, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, University of Ferrara, Ferrara, ItalyHematology, Azienda Ospedaliera “Pugliese Ciaccio”, Presidio Ospedaliero A. Pugliese - Unità Operativa di Ematologia, Catanzaro, ItalyGIMEMA Data Center, GIMEMA Foundation, Rome, ItalyGIMEMA Data Center, GIMEMA Foundation, Rome, ItalyHematology, Department of Translational and Precision Medicine, Sapienza University, Rome, ItalyDepartment of Molecular Medicine, Sapienza University, Rome, ItalyHematology, Department of Translational and Precision Medicine, Sapienza University, Rome, ItalyIbrutinib may revert the T-helper (Th)2 polarization observed in chronic lymphocytic leukemia (CLL) by targeting the IL-2-inducible kinase, that shows a significant homology with the Bruton tyrosine kinase. In the front-line GIMEMA LLC1114 trial (ibrutinib+rituximab for 6 months, followed by ibrutinib maintenance), we investigated the modulation of T-cell cytokine production in 208 peripheral blood paired samples from 71 CLL patients: 71 samples prior to treatment (Day 0, D0) and at day +14 (D14; n=50), at month +8 (M8; 30), +12 (M12; 25), +18 (M18; 22) and +24 (M24; 10) of treatment. We documented a progressive decrease of CD3+CD4+IL-4+ T cells (Th2), that was significant at M8 and at M12 (p=0.019, p=0.002), a relative increase in the CD3+CD4+IFNγ+ T cells (Th1) and a decrease of CD3+CD4+IL-17+ (Th17) cells that was maintained up to M18 (M8 vs D0 p=0.003, M12 vs D0 p=0.003, M18 vs D0 p=0.004) of ibrutinib treatment. The Th2/Th1 ratio significantly decreased already after 14 days of treatment and was maintained thereafter (D14 vs D0 p=0.037, M8 vs D0 p=0.001, M12 vs D0 p=0.005, M18 vs D0 p=0.002). The Th2/Th1 modulation over time was significant only among patients with unmutated IGHV. The Th2/Th1 ratio below a cut-off of 0.088 at M8 was associated with the achievement of a complete response (CR) (p=0.016). Ibrutinib may shape the CLL T-cell profile, limiting Th2 activation and inducing a shift in the Th2/Th1 ratio. The association between the Th2/Th1 ratio decrease and the CR achievement suggests the in vivo generation of a potential host anti-tumor immune activation induced by ibrutinib.https://www.frontiersin.org/articles/10.3389/fonc.2021.637186/fullchronic lymphocytic leukemiaibrutinibTh1Th2T lymphocytes |
| spellingShingle | Maria Cristina Puzzolo Ilaria Del Giudice Nadia Peragine Paola Mariglia Maria Stefania De Propris Luca Vincenzo Cappelli Livio Trentin Gianluigi Reda Antonio Cuneo Stefano Molica Alfonso Piciocchi Valentina Arena Francesca Romana Mauro Anna Guarini Robin Foà TH2/TH1 Shift Under Ibrutinib Treatment in Chronic Lymphocytic Leukemia Frontiers in Oncology chronic lymphocytic leukemia ibrutinib Th1 Th2 T lymphocytes |
| title | TH2/TH1 Shift Under Ibrutinib Treatment in Chronic Lymphocytic Leukemia |
| title_full | TH2/TH1 Shift Under Ibrutinib Treatment in Chronic Lymphocytic Leukemia |
| title_fullStr | TH2/TH1 Shift Under Ibrutinib Treatment in Chronic Lymphocytic Leukemia |
| title_full_unstemmed | TH2/TH1 Shift Under Ibrutinib Treatment in Chronic Lymphocytic Leukemia |
| title_short | TH2/TH1 Shift Under Ibrutinib Treatment in Chronic Lymphocytic Leukemia |
| title_sort | th2 th1 shift under ibrutinib treatment in chronic lymphocytic leukemia |
| topic | chronic lymphocytic leukemia ibrutinib Th1 Th2 T lymphocytes |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.637186/full |
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