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- W4313366132 abstract "Abstract T-cell activation is needed for responses to antigen and controls responses to foreign antigen and cancer neo-antigens in immunotherapy. The full range of signaling events that inhibit T-cell activation and limit anti-tumor reactivity is unclear. Previous studies have identified the importance of phosphatases and E-3 ligases as inhibitors of activation. In this study, we show by a combination of tandem affinity chromatography, co-precipitation and proximity ligation analysis (PLA) that RASAL1, a novel GTPase-activating protein (GAP), binds to ZAP-70 of the TCR complex and inhibits anti-CD3 activation of ERKs and proliferation in T-cells. RASAL1 inhibited via two pathways where it binds and inhibits ZAP-70 activity, and acts as a GAP to inhibit the p21ras-ERK pathway. As a negative regulator, its expression is induced as a consequence of T-cell activation, where it reduced in vitro responses to anti-CD3 and to antigenic peptides presented by dendritic cells (DCs), while having no effect on T-cell dwell times. Further, we show that siRNA knock-down of RASAL1 expression increased in vivo CD4+ T-cell responses to peptide antigen while reducing the pulmonary metastasis of B16 melanoma and the growth of solid EL-4 lymphoma tumors. This anti-tumor effect was accompanied by a marked increase in CD8+ tumor-infiltrating T-cells (TILs) expressing effector molecules granzyme B (GZMB) and interferon γ-1 (IFNγ1). These findings identify RASAL1 as a new negative regulator of T-cell activation and tumor immunity." @default.
- W4313366132 created "2023-01-06" @default.
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- W4313366132 date "2019-05-01" @default.
- W4313366132 modified "2023-10-01" @default.
- W4313366132 title "GTPase-activating protein (RASAL1) associates with ZAP-70 of the TCR and negatively regulates T-cell proliferation and anti-tumor immunity" @default.
- W4313366132 doi "https://doi.org/10.4049/jimmunol.202.supp.184.4" @default.
- W4313366132 hasPublicationYear "2019" @default.
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