Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL.

Maissa Mhibik,Adrian Wiestner,Clare Sun

doi:10.3390/ijms21010068

Abstract

B-cell receptor (BCR) signaling and tumor–microenvironment crosstalk both drive chronic lymphocytic leukemia (CLL) pathogenesis. Within the microenvironment, tumor cells shape the T-cell compartment, which in turn supports tumor growth and survival. Targeting BCR signaling using Bruton tyrosine kinase inhibitors (BTKi) has become a highly successful treatment modality for CLL. Ibrutinib, the first-in-class BTKi, also inhibits Tec family kinases such as interleukin-2–inducible kinase (ITK), a proximal member of the T-cell receptor signaling cascade. It is increasingly recognized that ibrutinib modulates the T-cell compartment of patients with CLL. Understanding these T-cell changes is important for immunotherapy-based approaches aiming to increase the depth of response and to prevent or treat the emergence of resistant disease. Ibrutinib has been shown to improve T-cell function in CLL, resulting in the expansion of memory T cells, Th1 polarization, reduced expression of inhibitory receptors and improved immune synapse formation between T cells and CLL cells. Investigating the modulation of BTKi on the T-cell antitumoral function, and having a more complete understanding of changes in T cell behavior and function during treatment with BTKi therapy will inform the design of immunotherapy-based combination approaches and increase the efficacy of CLL therapy.

Highlights

Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy characterized by the expansion of mature monoclonal B lymphocytes in the blood, bone marrow and lymphoid tissues
Circulating memory T cells are composed of central memory (CM), effector memory (EM) and effector memory RA (EMRA) that can be defined by their pattern of expression of the lymph node homing receptors CCR7 and CD45RA [28,29]
Expansion of differentiated memory T cells and a potential shift towards Th1 polarization have been observed in treated patients

Summary

Introduction

Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy characterized by the expansion of mature monoclonal B lymphocytes in the blood, bone marrow and lymphoid tissues. Interactions between tumor cells and their microenvironment trigger B-cell receptor (BCR) activation and support tumor growth and survival [1]. Inhibition of BCR signaling has become a highly successful treatment strategy for CLL and other B-cell malignancies. Among the first approved BCR kinase inhibitors, ibrutinib inhibits Bruton tyrosine kinase (BTK), and has achieved high response rates and durable remissions in CLL patients [2]. Whether directly through the inhibition of kinases other than BTK or indirectly through suppression of tumor microenvironment cross-talk, affects immune cells, of which T cells have been the most studied [4]. T cells provide pro-survival signals through soluble factors such as interleukin-4 (IL-4) and interferon-gamma (IFN- γ), which upregulate anti-apoptotic Bcl-2 in CLL cells, [5,6] and by direct interactions via CD40L-CD40 [7]. We discuss the effect of ibrutinib on T cells and the potential of harnessing these changes to improve disease control by combining ibrutinib with immunotherapy

Improved Antitumor T-Cell Responses during Treatment with Ibrutinib

Absolute Number of T Cells

T-Cell Receptor Repertoire

Memory T Cells

Th1 and Th2 Polarization

Th17 and Tregs Balance

T-Cell Function

Combining BTK Inhibitors with Immunomodulatory Drugs

Combining BTK Inhibitors with Checkpoint Inhibitors

Conclusions