|
| Status |
Public on Jun 01, 2018 |
| Title |
Blocking IFNRA1 inhibits Multiple Myeloma-driven regulatory T-cell expansion and immunosuppression |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Despite significant advances in the treatment of multiple myeloma (MM), most patients succumb to disease progression. One of the major immunosuppressive mechanisms that is believed to play a role in myeloma progression, is the expansion of regulatory T-cells (Tregs). In this study, we demonstrate that myeloma cells drive Treg expansion and activation by secreting type-1 interferon (IFN). Blocking IFNAR1 (interferon alpha and beta receptor 1) on Tregs significantly decreases both, myeloma-associated Treg immunosupporessive function and myeloma progression. Using syngeneic transplantable murine myeloma models and bone marrow (BM) aspirates of multiple myeloma patients, we found that Tregs were expanded and activated in the BM microenvironment at early stages of myeloma development. Selective depletion of Tregs led to a complete remission and prolonged survival in mice injected with myeloma cells. Further analysis of the interaction between myeloma cells and Tregs using gene sequencing and enrichment analysis uncovered a feedback loop, wherein myeloma-cell-secreted type-1 IFN induced proliferation and expansion of Tregs. By using IFNAR1-blocking antibody treatment and IFNAR1 knockout Tregs, we demonstrated a significant decrease in myeloma-associated Treg proliferation, which was associated with longer survival of myeloma-injected mice. Our results thus suggest that blocking type-1 IFN signaling represents a potential strategy to target immunosuppressive Trage function in MM.
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| |
|
| Overall design |
RNA sequencing of 3 BM of Vk*MYC-injected and 3 BM of control mice
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| |
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| Contributor(s) |
Kawano Y, Zavidij O, Ghobrial I |
| Citation missing |
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| |
| Submission date |
Jan 23, 2018 |
| Last update date |
Mar 19, 2019 |
| Contact name |
Irene Ghobrial |
| E-mail(s) |
irene_ghobrial@dfci.harvard.edu
|
| Phone |
6176326777
|
| Organization name |
Dana-Farber Cancer Institute
|
| Department |
Medical Oncology
|
| Lab |
Ghobrial Lab
|
| Street address |
4 Blackfan Circle, 2nd Floor, Suite 240
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
|
| Samples (6)
|
|
| Relations |
| BioProject |
PRJNA431309 |
| SRA |
SRP131172 |
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