Inefficient CAR-proximal signaling blunts antigen sensitivity

Gudipati, Venugopal; Rydzek, Julian; Doel-Perez, Iago; Gonçalves, Vasco Dos Reis; Scharf, Lydia; Königsberger, Sebastian; Lobner, Elisabeth; Kunert, Renate; Einsele, Hermann; Stockinger, Hannes; Hudecek, Michael; Huppa, Johannes B.

doi:10.1038/s41590-020-0719-0

Cited by 103 publications

(103 citation statements)

References 55 publications

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“…The importance of ZAP-70 in CAR-T activation has been further addressed by a very recent study: Using quantitative singlemolecule live-cell imaging, CAR-T cells have been shown to have ∼1,000 times reduced antigen sensitivity compared to normal T cells, and data suggest that the underlying mechanism relates to reduced recruitment of ZAP-70 to CARs. This study enlightens the importance of ZAP-70 in CAR-T activation and suggests it as a promising target for improving CAR-T antigen recognition (62).…”

Section: Car-t Cellsmentioning

confidence: 66%

ZAP-70 Shapes the Immune Microenvironment in B Cell Malignancies

2020

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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.

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Section: Car-t Cellsmentioning

confidence: 66%

ZAP-70 Shapes the Immune Microenvironment in B Cell Malignancies

2020

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“…On the other hand, TCR expressed by conventional CD8 + T cells recognize peptides presented by MHC class I molecules, which reflect the whole protein content of a cell, both from the cell surface and from the cytosol. In addition, important issues such as CAR degradation upon engagement, [34][35][36] suboptimal CAR signaling, 37 or tonic CAR signaling that lead to T cell dysfunction 38 in treating refractory B cell malignancy, 12,13,39,40 although less than 50% of patients achieve long-term disease control. 13,39 Continuous and rapid improvements in the design of CAR should improve anti-tumor function of CAR T cells in vivo in a close future.…”

Section: Tumor Cell Targeting By Natural and Engineered Conventionamentioning

confidence: 99%

Beyond CAR T cells: Engineered Vγ9Vδ2 T cells to fight solid tumors

Rafia

Harly

Scotet

2020

Immunological Reviews

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Cancer, a general term used to describe a large group of life-threatening malignancies, represented the second leading cause of death in the world in 2018, according to the World Health Organization. Cancer cells can establish and develop in almost any organ or tissue of every individual. Solid tumors, which represent more than 90% of adult cancers, correspond to masses of cancer cells deeply enmeshed with tissues of origin (eg, lung, breast, prostate, colon, bladder). Liquid tumors such as lymphomas and leukemias develop in body fluids (eg, blood). Physiologically speaking, abnormal cells with somatic mutations and aberrant/dysregulated pathways grow uncontrollably, destroy adjacent tissues, and eventually spread into other organs. 1 Because of the difficulty to establish diagnosis at early stages, cancer eradication is very challenging. Standard treatments to cure cancer are based on chemotherapy or radiotherapy, but their poor specificity for cancer cells induces a substantial toxicity. Furthermore, because of inter-individual variability and tumor heterogeneity, the outcomes of these treatments are often unpredictable. A major recent advance of biomedical research is a better understanding of key roles played by the immune system in tumor surveillance, and the mechanisms developed by tumor cells to evade this surveillance and hack immune pathways to promote tumorigenesis. 2 Accordingly, novel strategies have emerged over the last decades that aim at enhancing, complementing, or restoring the ability of patient's immunity to generate specific and efficient responses,

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“…As typical binding affinities for antibodies are in the low nM range, this also means that standard single-chain CARs bind antigens with approximately 1000-fold higher affinity than the mM TCR-pMHC interaction. Despite this fact, T cell activation through a CAR requires as much as 1000-fold higher antigen density than through a natural TCR recognizing pMHC [ 137 ]. Even in an experimental scenario where the CAR and TCR used the same antigen binding domain (an engineered TCR with high-nM affinity for a pMHC ligand) and with the CAR expressed at 10-fold higher surface levels than TCR, CAR-T cells were 10-fold to 100-fold less sensitive than T cells receiving signals through the high-affinity TCR complex [ 138 ].…”

Section: Functional Consequences Of Car Design and Structurementioning

confidence: 99%

T Cell Activation Machinery: Form and Function in Natural and Engineered Immune Receptors

Chandler

Call

2020

IJMS

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The impressive success of chimeric antigen receptor (CAR)-T cell therapies in treating advanced B-cell malignancies has spurred a frenzy of activity aimed at developing CAR-T therapies for other cancers, particularly solid tumors, and optimizing engineered T cells for maximum clinical benefit in many different disease contexts. A rapidly growing body of design work is examining every modular component of traditional single-chain CARs as well as expanding out into many new and innovative engineered immunoreceptor designs that depart from this template. New approaches to immune cell and receptor engineering are being reported with rapidly increasing frequency, and many recent high-quality reviews (including one in this special issue) provide comprehensive coverage of the history and current state of the art in CAR-T and related cellular immunotherapies. In this review, we step back to examine our current understanding of the structure-function relationships in natural and engineered lymphocyte-activating receptors, with an eye towards evaluating how well the current-generation CAR designs recapitulate the most desirable features of their natural counterparts. We identify key areas that we believe are under-studied and therefore represent opportunities to further improve our grasp of form and function in natural and engineered receptors and to rationally design better therapeutics.

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Inefficient CAR-proximal signaling blunts antigen sensitivity

Cited by 103 publications

References 55 publications

ZAP-70 Shapes the Immune Microenvironment in B Cell Malignancies

ZAP-70 Shapes the Immune Microenvironment in B Cell Malignancies

Beyond CAR T cells: Engineered Vγ9Vδ2 T cells to fight solid tumors

T Cell Activation Machinery: Form and Function in Natural and Engineered Immune Receptors

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