ZAP-70 Shapes the Immune Microenvironment in B Cell Malignancies

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.

Identification of a Prognostic Model Based on Fatty Acid Metabolism-Related Genes of Head and Neck Squamous Cell Carcinoma

“…Chen et al demonstrated that ZAP70 could promote cell survival, microenvironment interactions, protein synthesis and further drive disease progression in chronic lymphocytic leukemia cells (Chen et al, 2021). ZAP-70 could also shape the immune microenvironment in B cell malignancies ( Chen et al, 2020 ). Liu et al proposed that ZAP70-deficiency may improve reverse cholesterol transport and decrease the inflammatory response of T cells ( Liu et al, 2019 ).…”

The Role of RhoH in TCR Signalling and Its Involvement in Diseases

“…Interestingly, ZAP−70 may participate in BCR signalling by limiting the ability of BCR to induce negative B-cell selection and cell death [ 109 ]. Additionally, ZAP−70 may regulate BCR signalling via its kinase activity or as a scaffold protein recruiting the other tyrosine kinases [ 110 ]. Given that RhoH is widely known to regulate ZAP−70 activation, it may also be implicated in SLE.…”

Strategies for Dodging the Obstacles in CAR T Cell Therapy

“…The activation domain used in the structure of CARs has the critical role of T cell activation upon target antigen encountering and it is mostly derived from the CD3ζ part of the T cell receptor (TCR) CD3 complex ( 13 ). However, other activation domains that have been used include FcϵRIγ, the ζ-chain of TCR-associated protein kinase 70 kDa (ZAP70), and DAP12 ( 13 – 17 ). The early CAR T cells (termed “first-generation CARs”) did not have any co-stimulatory domain and did not show promising antitumor efficacy mainly due to the lack of adequate persistence and activation ( 18 ).…”