ZAP-70 Shapes the Immune Microenvironment in B Cell Malignancies.

Jingyu Chen,Andrew Moore,Ingo Ringshausen

doi:10.3389/fonc.2020.595832

Abstract

Zeta-chain-associated protein kinase-70 (ZAP-70) is a tyrosine kinase mainly expressed in T cells, NK cells and a subset of B cells. Primarily it functions in T cell receptor (TCR) activation through its tyrosine kinase activity. Aberrant expression of ZAP-70 has been evidenced in different B cell malignancies, with high expression of ZAP-70 in a subset of patients with Chronic Lymphocytic Leukemia (CLL), associating with unfavorable disease outcomes. Previous studies to understand the mechanisms underlying this correlation have been focused on tumor intrinsic mechanisms, including the activation of B cell receptor (BCR) signaling. Recent evidence also suggests that ZAP-70, intrinsically expressed in tumor cells, can modulate the cross-talk between malignant B cells and the immune environment, implying a more complex role of ZAP-70 in the pathogenesis of B cell malignancies. Meanwhile, the indispensible roles of ZAP-70 in T cell and NK cell activation also demonstrate that the autologous expression of ZAP-70 in the immune environment can be a central target in modulation of tumor immunity. Here we review the evidences of the link between ZAP-70 and tumor immunology in the microenvironment in B cell malignancies. Considering an emerging role of immunotherapies in treating these conditions, understanding the distinct molecular functions of ZAP-70 in a broader cellular context could ultimately benefit patient care.

Highlights

Zeta-chain-associated protein kinase-70 (ZAP-70) is a tyrosine kinase mainly expressed in T cells and NK cells [1, 2]
In Chronic Lymphocytic Leukemia (CLL), ZAP-70 positive patients have significantly higher CCL3 and CCL4 plasma levels [43], and CCL3 plasma levels correlate with other risk factors [44]. These findings suggest a potential role of tumor autologous ZAP-70, mediating immune-responses and fostering a tumor-supportive microenvironment through modulation of the expression of T cell chemokines
4 ZAP-70 enhances B cell receptor (BCR) signaling upon IgM activation; 4 Interactions with BCR-related proteins; 4 ZAP-70 correlates with chemokine receptor type 7 (CCR7), CXCR4 expression and enhanced cell migration; 4 Modulation of Toll-like receptor (TLR)-induced response through mediating SYK activation, IgM secretion, and

Summary

Introduction

Zeta-chain-associated protein kinase-70 (ZAP-70) is a tyrosine kinase mainly expressed in T cells and NK cells [1, 2]. Studies have implied that tumor intrinsic ZAP70 expression modulates the cross-talk between malignant B cells and their environment, suggesting a new angle to understand the role of ZAP-70 in these diseases. In CLL, ZAP-70 expression is associated with enhanced BCR signaling upon IgM activation, evidenced by a positive correlation between ZAP-70 expression, phosphorylation of SYK, BLNK, and PLCγ2 and calcium response [4, 27].

Results

Conclusion