 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Dec 02, 2020 |
| Title |
Combined BRAF, MEK and CDK4/6 inhibition depletes intratumoral immune-potentiating myeloid populations in melanoma |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Combined inhibition of BRAF, MEK and CDK4/6 is currently under evaluation in clinical trials for patients with melanoma harboring a BRAFV600 mutation. While this triple therapy has potent tumor-intrinsic effects, the impact of this combination on anti-tumor immunity remains unexplored. Here, using a syngeneic BrafV600ECdkn2a-/-Pten-/- melanoma model, we demonstrated that triple therapy promoted durable tumor control through tumor-intrinsic mechanisms and promoted immunogenic cell death and T-cell infiltration. Despite this, tumors treated with triple therapy were unresponsive to immune checkpoint blockade (ICB). Flow cytometric and single-cell RNA-seq analyses of tumor-infiltrating immune populations revealed that triple therapy markedly depleted pro-inflammatory macrophages and cross-priming CD103+ dendritic cells (DCs), the absence of which correlated with poor overall survival and clinical responses to ICB in melanoma patients. Indeed, immune populations isolated from tumors of mice treated with triple therapy failed to stimulate T-cell responses ex vivo. While combined BRAF, MEK and CDK4/6 inhibition demonstrates favourable tumor-intrinsic activity, these data suggest that collateral effects on tumor-infiltrating myeloid populations may impact on anti-tumor immunity. These findings have important implications for the design of combination strategies and clinical trials that incorporate BRAF, MEK and CDK4/6 inhibition with immunotherapy for the treatment of patients with melanoma.
|
| |
|
| Overall design |
Single-cell RNA-seq and paired TCR-seq on the CD45.2+ immune cells from YOVAL1.1 melanoma tumors treated for 7 days with vehicle or triple (one sample per group representative of 10 tumors pooled)
|
| |
|
| Contributor(s) |
Sheppard KE, Oliaro J, McArthur GA, Lelliott EJ, Mangiola S |
| Citation(s) |
33303574 |
| |
| Submission date |
Dec 01, 2020 |
| Last update date |
Mar 11, 2021 |
| Contact name |
Emily Jane Lelliott |
| E-mail(s) |
emily.lelliott@petermac.org
|
| Phone |
0402164944
|
| Organization name |
Peter MacCallum Cancer Centre
|
| Department |
Research
|
| Street address |
305 Grattan Street
|
| City |
Melbourne |
| State/province |
VIC |
| ZIP/Postal code |
3000 |
| Country |
Australia |
| |
|
| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
|
| Samples (2) |
|
| Relations |
| BioProject |
PRJNA681909 |
| SRA |
SRP295420 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE162467_TCR_source_table.rds.gz |
3.2 Mb |
(ftp)(http) |
RDS |
| GSE162467_seurat_object_for_publication.rda.gz |
471.6 Mb |
(ftp)(http) |
RDA |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
|
|
|
|
 |
