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| Status |
Public on May 01, 2020 |
| Title |
Dual Relief of T-Lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in cancer patients could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggests a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor-specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison to their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor-specific CD8 T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated head and neck cancer patients. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors.
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| Overall design |
4 head and neck, cervical, and ovarian cancers
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| Contributor(s) |
Balança C, Scarlata C, Michelas M, Tosolini M, Ayyoub M |
| Citation(s) |
32295784, 33332284 |
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| Submission date |
Apr 06, 2020 |
| Last update date |
Mar 16, 2021 |
| Contact name |
Clara-Maria Scarlata |
| E-mail(s) |
[email protected]
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| Organization name |
INSERM
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| Street address |
2 avenue Hubert Curien
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| City |
Toulouse |
| State/province |
toulouse |
| ZIP/Postal code |
31037 |
| Country |
France |
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| Platforms (1) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA623361 |
| SRA |
SRP255417 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE148162_RAW.tar |
8.1 Mb |
(http)(custom) |
TAR (of TSV) |
| GSE148162_UMAP_coordinate.tsv.gz |
140.2 Kb |
(ftp)(http) |
TSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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