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| Status |
Public on Jul 23, 2021 |
| Title |
Targeting the Atf7ip-Setdb1 complex augments anti-tumor immunity by boosting tumor immunogenicity |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Other
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| Summary |
Despite substantial progress that has been made in understanding how tumors escape immune surveillance, measures to counteract tumor immune evasion have been limited. Suppression of tumor antigen expression is a common adaptive mechanism that cancers use to evade detection and destruction by the immune system. Epigenetic modifications play a critical role in in various aspects of immune invasion, including the regulation of tumor antigen expression. To identify novel epigenetic regulators of tumor antigen expression, we established a transplantable syngeneic tumor model of immune escape with silenced antigen expression and used this system as a platform for a CRISPR-Cas9 suppressor screen targeting genes encoding epigenetic modifiers. We found that genetic disruption of the chromatin modifiers Atf7ip or its interacting partner Setdb1 in tumor cells restored tumor antigen expression, resulting in augmented tumor immunogenicity concomitant with elevated endogenous retroviral antigens (ERVs), mRNA intron retention. ERVs disinhibition was associated with a robust type I interferon response and increased T cell infiltration, leading to rejection of cells lacking intact Atf7ip or Setdb1. ATF7IP or SETDB1 expression inversely correlated with antigen processing and presentation pathways, interferon signaling, and T cell infiltration and cytotoxicity in human cancers. Our results provide a rationale for targeting Atf7ip or Setdb1 in cancer immunotherapy.
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| Overall design |
one set of H3K9 me3 ChIP sequencing data, 7 groups with replicates including input, control, Atf7ip KO_1 Atf7ip KO_2, Setdb1 KO_2, Setdb1 KO_4 and Setdb1 KO_5 ; two set of RNA sequencing data including control and Atf7ip ko and control with Setdb1 KO (replicates for each group); one set of CRISPR loss of function screen sequencing data, replicates for each group; one set of Hi-C sequencing data including control, Atf7ip KO and Setdb1 KO
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| Contributor(s) |
Hu H, Li F, Khodadadi-Jamayran A, Wong KK |
| Citation(s) |
34462284 |
| |
| Submission date |
Jul 06, 2021 |
| Last update date |
Oct 25, 2021 |
| Contact name |
Alireza Khodadadi-Jamayran |
| Organization name |
New York University, NYU Langone Medical Center
|
| Department |
Division of Advanced Research Technologies (DART)
|
| Lab |
Applied Bioinformatics Laboratories (ABL)
|
| Street address |
550 1st Ave, MSB 304
|
| 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 (41)
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| Relations |
| BioProject |
PRJNA744222 |
| SRA |
SRP327190 |
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