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GTPase-activating protein Rasal1 associates with ZAP-70 of the TCR and negatively regulates T-cell tumor immunity

Thaker, Youg Raj and Raab, Monika and Strebhardt, Klaus and Rudd, Christopher E (2019) 'GTPase-activating protein Rasal1 associates with ZAP-70 of the TCR and negatively regulates T-cell tumor immunity.' Nature Communications, 10 (1). 4804-. ISSN 2041-1723

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Abstract

Immunotherapy involving checkpoint blockades of inhibitory co-receptors is effective in combating cancer. Despite this, the full range of mediators that inhibit T-cell activation and influence anti-tumor immunity is unclear. Here, we identify the GTPase-activating protein (GAP) Rasal1 as a novel TCR-ZAP-70 binding protein that negatively regulates T-cell activation and tumor immunity. Rasal1 inhibits via two pathways, the binding and inhibition of the kinase domain of ZAP-70, and GAP inhibition of the p21ras-ERK pathway. It is expressed in activated CD4 + and CD8 + T-cells, and inhibits CD4 + T-cell responses to antigenic peptides presented by dendritic cells as well as CD4 + T-cell responses to peptide antigens in vivo. Furthermore, siRNA reduction of Rasal1 expression in T-cells shrinks B16 melanoma and EL-4 lymphoma tumors, concurrent with an increase in CD8 + tumor-infiltrating T-cells expressing granzyme B and interferon γ-1. Our findings identify ZAP-70-associated Rasal1 as a new negative regulator of T-cell activation and tumor immunity.

Item Type: Article
Uncontrolled Keywords: T-Lymphocytes; CD4-Positive T-Lymphocytes; Animals; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Melanoma, Experimental; Extracellular Signal-Regulated MAP Kinases; GTPase-Activating Proteins; Receptors, Antigen, T-Cell; RNA, Small Interfering; Lymphocyte Activation; Female; Male; ZAP-70 Protein-Tyrosine Kinase; Protein Domains
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 16 Jul 2021 13:10
Last Modified: 06 Jan 2022 14:06
URI: http://repository.essex.ac.uk/id/eprint/26431

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