 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Sep 24, 2020 |
| Title |
Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
T-cell exclusion from the tumor microenvironment (TME) is a significant obstacle in cancer immunotherapy. Evidence indicates crucial roles of Batf3-dependent dendritic cells for inducing antitumor T-cell immunity. However, strategies to maximize the engagement of Batf3-dependent dendritic cells into such ‘cold tumors’ remain elusive. Using multiple syngeneic orthotopic mouse models of non-T cell-inflamed tumors, we hypothesized that in situ induction and activation of tumor-residing Batf3-dependent dendritic cells overcomes poor T-cell infiltration. In situ immunomodulation with Flt3L, radiotherapy, and TLR3/CD40 stimulation induces an influx of stem-like Tcf1+Slamf6+CD8+ T cells, triggers robust regression not only of primary, but also untreated distant tumors, and renders non-T cell-inflamed tumors responsive to anti-PD-L1 therapy. Furthermore, serial ISIM reshapes repertoires of intratumoral T cells, overcomes acquired resistance to anti-PD-L1 therapy, resulting in eradication of tumors, and establishes tumor-specific immunological memory. These findings provide new insights into Batf3-dependent dendritic cells biology as a critical determinant to the formation of a T cell-inflamed TME.
|
| |
|
| Overall design |
To investigate treatment effects on tumor infiltrating immune cell populations, we sorted live tumor-infiltrating CD45+ cells from subcutaneous (s.c.) AT-3 tumors, which were treated with either ISIM (I), aPD-L1 (P), both (IP) or left untreated (NT) and performed scRNA-seq. Droplet-based 3’ end massively parallel single-cell RNA sequencing was performed by encapsulating sorted live CD45+ cells into droplets and libraries prepared using Chromium Single Cell 30 Reagent Kits V3 according to manufacturer’s protocol (10x Genomics).
|
| |
|
| Contributor(s) |
Oba T, Long MD, Ito F |
| Citation(s) |
33110069 |
| |
| Submission date |
Jul 22, 2020 |
| Last update date |
Nov 16, 2020 |
| Contact name |
Mark D Long |
| E-mail(s) |
mark.long@roswellpark.org
|
| Organization name |
Roswell Park Comprehensive Cancer Center
|
| Department |
Bioinformatics & Biostatistics
|
| Street address |
Elm & Carlton Streets
|
| City |
Buffalo |
| State/province |
NY |
| ZIP/Postal code |
14263 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
|
| Samples (4)
|
|
| Relations |
| BioProject |
PRJNA647616 |
| SRA |
SRP273011 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE154879_RAW.tar |
59.0 Mb |
(http)(custom) |
TAR (of H5) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
|
|
|
|
 |
Less...
More...