TH2/TH1 Shift Under Ibrutinib Treatment in Chronic Lymphocytic Leukemia.

Maria Cristina Puzzolo,Antonio Cuneo,Livio Trentin,Maria Stefania De Propris,Gianluigi Reda,Ilaria Del Giudice,Stefano Molica,Nadia Peragine,Valentina Arena,Paola Mariglia,Luca Vincenzo Cappelli,Francesca Romana Mauro,Robin Foà,Alfonso Piciocchi,Anna Guarini

doi:10.3389/fonc.2021.637186

Abstract

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.

Highlights

In chronic lymphocytic leukemia (CLL), malignant B cells and the surrounding tissue microenvironment closely interact
The absolute numbers of CD4+ T cells showed a significant increase compared to pre-treatment samples at day +14 (D14) (p=0.023), followed by a subsequent decrease starting from month +8 (M8), that became significant at M12 (p=0.037) (Figure 2B, Figure S2)
We detected a progressive increase in the percentage of CD3+CD4+interferon g (IFNg)+ T cells (Th1), with a decrease of CD3+CD4+IL-4+ T cells (Th2) cells

Summary

Introduction

In chronic lymphocytic leukemia (CLL), malignant B cells and the surrounding tissue microenvironment closely interact. The leukemic clone develops strategies of evasion or suppression of the immune system, in particular toward the anti-tumor effects of T lymphocytes [4,5,6,7]. CLL cells produce IL-6 and stimulate IL-4 production by T cells, skewing the immune system toward a Th2-phenotype, that releases IL-4, IL-5, IL-10 and IL-13 [13,14,15,16]. IL10, a cytokine produced by Th2 cells, is a powerful inhibitor of the Th1 cytokine synthesis - including interferon g (IFNg), tumor necrosis factor a (TNFa), IL-2 and lymphotoxin (LTa) [14] and stimulates B-cell proliferation and differentiation, promoting the skewing toward a Th2 response

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Results

Conclusion