TH2/TH1 Shift Under Ibrutinib Treatment in Chronic Lymphocytic Leukemia

• Published in: Frontiers in oncology Vol. 11; p. 637186
• Main Authors: Puzzolo, Maria Cristina, Del Giudice, Ilaria, Peragine, Nadia, Mariglia, Paola, De Propris, Maria Stefania, Cappelli, Luca Vincenzo, Trentin, Livio, Reda, Gianluigi, Cuneo, Antonio, Molica, Stefano, Piciocchi, Alfonso, Arena, Valentina, Mauro, Francesca Romana, Guarini, Anna, Foà, Robin
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 15-04-2021
• Subjects: chronic lymphocytic leukemia; ibrutinib; Oncology; T lymphocytes; Th1; Th2; T lymphocytes; ibrutinib; chronic lymphocytic leukemia; Th1; Th2
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2021.637186

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
D0 p=0.003, M12
D0 p=0.003, M18
D0 p=0.004) of ibrutinib treatment. The Th2/Th1 ratio significantly decreased already after 14 days of treatment and was maintained thereafter (D14
D0 p=0.037, M8
D0 p=0.001, M12
D0 p=0.005, M18
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
generation of a potential host anti-tumor immune activation induced by ibrutinib.