SATB1 Expression Governs Epigenetic Repression of PD-1 in Tumor-Reactive T Cells
| Autor: | Ricardo A. Chaurio, Jairo Perez-Sanz, Kyle K. Payne, Alfredo Perales-Puchalt, Hengrui Zhu, Mark E. Borowsky, Rugang Zhang, Terri M. Laufer, Tom L. Stephen, Ana E. Vara-Ailor, Evgeniy Eruslanov, Jose R. Conejo-Garcia, Michael J. Allegrezza, Jenny M. Nguyen |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Enzyme-Linked Immunospot Assay T-Lymphocytes T cell Programmed Cell Death 1 Receptor Immunology Cell SMAD Epigenetic Repression Biology Lymphocyte Activation Article Mice 03 medical and health sciences Lymphocytes Tumor-Infiltrating 0302 clinical medicine Neoplasms medicine Animals Immunoprecipitation Humans Immunology and Allergy Psychological repression Mice Knockout Genome Effector Matrix Attachment Region Binding Proteins Chromatin Mice Inbred C57BL 030104 developmental biology Infectious Diseases medicine.anatomical_structure Gene Expression Regulation Regulatory sequence 030220 oncology & carcinogenesis Cancer research |
| Zdroj: | Immunity. 46:51-64 |
| ISSN: | 1074-7613 |
| DOI: | 10.1016/j.immuni.2016.12.015 |
| Popis: | Despite the importance of programmed cell death-1 (PD-1) in inhibiting T cell effector activity, the mechanisms regulating its expression remain poorly defined. We found that the chromatin organizer special AT-rich sequence-binding protein-1 (Satb1) restrains PD-1 expression induced upon T cell activation by recruiting a nucleosome remodeling deacetylase (NuRD) complex to Pdcd1 regulatory regions. Satb1 deficienct T cells exhibited a 40-fold increase in PD-1 expression. Tumor-derived transforming growth factor β (Tgf-β) decreased Satb1 expression through binding of Smad proteins to the Satb1 promoter. Smad proteins also competed with the Satb1-NuRD complex for binding to Pdcd1 enhancers, releasing Pdcd1 expression from Satb1-mediated repression, Satb1-deficient tumor-reactive T cells lost effector activity more rapidly than wild-type lymphocytes at tumor beds expressing PD-1 ligand (CD274), and these differences were abrogated by sustained CD274 blockade. Our findings suggest that Satb1 functions to prevent premature T cell exhaustion by regulating Pdcd1 expression upon T cell activation. Dysregulation of this pathway in tumor-infiltrating T cells results in diminished anti-tumor immunity. |
| Databáze: | OpenAIRE |
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