The phosphatase PAC1 acts as a T cell suppressor and attenuates host antitumor immunity
- 13 January 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Immunology
- Vol. 21 (3), 287-297
- https://doi.org/10.1038/s41590-019-0577-9
Abstract
Cancer cells subvert immune surveillance through inhibition of T cell effector function. Elucidation of the mechanism of T cell dysfunction is therefore central to cancer immunotherapy. Here, we report that dual specificity phosphatase 2 (DUSP2; also known as phosphatase of activated cells 1, PAC1) acts as an immune checkpoint in T cell antitumor immunity. PAC1 is selectively upregulated in exhausted tumor-infiltrating lymphocytes and is associated with poor prognosis of patients with cancer. PAC1hi effector T cells lose their proliferative and effector capacities and convert into exhausted T cells. Deletion of PAC1 enhances immune responses and reduces cancer susceptibility in mice. Through activation of EGR1, excessive reactive oxygen species in the tumor microenvironment induce expression of PAC1, which recruits the Mi-2β nucleosome-remodeling and histone-deacetylase complex, eventually leading to chromatin remodeling of effector T cells. Our study demonstrates that PAC1 is an epigenetic immune regulator and highlights the importance of targeting PAC1 in cancer immunotherapy.Keywords
This publication has 49 references indexed in Scilit:
- Reactive oxygen species delay control of lymphocytic choriomeningitis virusCell Death & Differentiation, 2013
- Timing and Magnitude of Type I Interferon Responses by Distinct Sensors Impact CD8 T Cell Exhaustion and Chronic Viral InfectionCell Host & Microbe, 2012
- Insights into RNA Biology from an Atlas of Mammalian mRNA-Binding ProteinsCell, 2012
- Integrative genomics viewerNature Biotechnology, 2011
- An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patientsBreast Cancer Research and Treatment, 2009
- ChIP-seq: Using high-throughput sequencing to discover protein–DNA interactionsMethods, 2009
- RAD18 transmits DNA damage signalling to elicit homologous recombination repairNature, 2009
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- Quantitative PCR technique for detecting lymphocytic choriomeningitis virus in vivoJournal of Virological Methods, 2008
- PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetesNature Genetics, 2003