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Status |
Public on May 19, 2020 |
Title |
PD-L1 Engagement on T cells Promotes Self-tolerance and Suppression of Neighboring Macrophages and Effector T cells in Cancer |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
PD-1 ligation delimits immunogenic responses in T cells. However, the consequences of PD-L1 ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor-antigen, microbial signals, and sterile inflammatory cues. PD-L1+ T cells exerted tumor-promoting tolerance via three distinct mechanisms: (i) Binding of PD-L1 induced STAT3-dependent back-signaling in CD4+ T cells preventing activation, reducing Th1-polarization, and directing Th17-differentiation. PD-L1 signaling also induced an anergic Tbet-IFNg- phenotype in CD8+ T cells and was equally suppressive compared to PD-1 signaling. (ii) PD-L1+ T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis even in the absence of endogenous PD-L1. (iii) PD-L1+ T cells engaged PD-1+ macrophages inducing an alternative M2-like program, which had crippling effects on adaptive anti-tumor immunity. Collectively, we demonstrate that PD-L1+ T cells have diverse tolerogenic effects on tumor immunity.
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Overall design |
For RNA-Seq experiments, mouse PDL1 knockout and wild-type T cells were stimulated in vitro using anti-CD3 and anti-CD28. Alternatively, CD45+ leukocytes were FACS-sorted from mouse pancreatic tumors 3 weeks after orthotopic implantation.
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Contributor(s) |
Aykut B, Khodadadi-Jamayran A, Miller G |
Citation(s) |
32152508 |
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Submission date |
Feb 25, 2020 |
Last update date |
May 19, 2020 |
Contact name |
Alireza Khodadadi-Jamayran |
Organization name |
New York University, NYU Langone Medical Center
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Department |
Division of Advanced Research Technologies (DART)
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Lab |
Applied Bioinformatics Laboratories (ABL)
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Street address |
550 1st Ave, MSB 304
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City |
New York City |
State/province |
NY |
ZIP/Postal code |
10016 |
Country |
USA |
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Platforms (1) |
GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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Samples (17)
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Relations |
BioProject |
PRJNA608709 |
SRA |
SRP250701 |