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| Status |
Public on Dec 08, 2021 |
| Title |
Conditional deletion of Pdcd1 identifies the cell-intrinsic action of PD-1 on functional CD8 T cell subsets for anti-tumor efficacy |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
PD-1 blockade has a profound effect on the ability of the immune system to eliminate tumors but many questions remain about the cell types involved and the underlying mechanisms of immune activation. To shed some light on this, the cellular and molecular events following inhibition of PD-1 signaling was investigated in the MC-38 colon carcinoma model using constitutive (PD-1 KO) and conditional (PD1cKO) PD-1 KO mice as well as in wild type mice treated with an anti-PD-1 antibody. The impact on both tumor growth and the development of tumor immunity was assessed. In the PD-1cKO mice, a complete deletion of Pdcd1 in tumor infiltrating T cells (TILs) after tamoxifen treatment led to the inhibition of tumor growth of both small and large tumors. Extensive immune phenotypic analysis of the TILs by flow and mass cytometry identified 22-different T cell subsets of which specifically 5-CD8 positive ones expanded in all three models after PD-1 blockade. All 5 subsets expressed granzyme B and secreted IFNγ. Gene expression analysis of the tumor further supported the phenotypic analysis in both PD-1cKO and PD-1 Ab treated mice and showed an upregulation of pathways related to CD4 and CD8 T cell activation and enhanced signaling through co-stimulatory molecules and IFNγ. Altogether, using PD-1 cKO we define the intrinsic nature of PD-1 suppression of CD8 T cell responses in tumor immunity.
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| |
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| Overall design |
Total RNA from tumors from either wild-type MC38 mice treated with anti-PD1 antibody muDX400, or conditional Pdcd1 (PD1) KO mice, was sequenced.
|
| Web link |
https://doi.org/10.3389/fimmu.2021.752348
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| |
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| Contributor(s) |
Muise ES, Raghavan S, Sathe M, Blumenschein W, Pinheiro EM, de Waal Malefyt R |
| Citation(s) |
34912335 |
| |
| Submission date |
Mar 31, 2021 |
| Last update date |
Jan 07, 2022 |
| Contact name |
Eric Muise |
| E-mail(s) |
[email protected]
|
| Phone |
6179923514
|
| Organization name |
Merck
|
| Department |
GPGX
|
| Street address |
33 Ave. Louis Pasteur
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
|
| Samples (46)
|
|
| Relations |
| BioProject |
PRJNA718882 |
| SRA |
SRP312955 |
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