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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Feb 16, 2021 |
| Title |
Single cell RNA-seq analysis of the LLC-OVA tumor-infiltrating T-cell compartment. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Modulation and depletion of regulatory T cells (Tregs) constitute valid approaches in antitumor immunotherapy but suffer from severe adverse effects due to their lack of selectivity for the tumor-infiltrating (ti-)Treg population. We here employed single-cell RNA-sequencing to discern two ti-Treg populations, one of which is characterized by the unique expression of Ccr8 in conjunction with Treg activation markers. Ccr8 is also expressed by dysfunctional CD4+ and CD8+ T cells, but the CCR8 protein was only prominent on the highly activated and strongly T-cell suppressive ti-Treg subpopulation of mouse and human tumors, with no major CCR8-positivity found on peripheral Tregs. CCR8 expression resulted from TCR-mediated Treg triggering in an NF-kB-dependent fashion, but was not essential for the recruitment, activation nor suppressive capacity of these cells. We generated two CCR8-specific nanobodies (Nbs) that recognize distinct epitopes on the CCR8 extracellular domain. These Nbs were formulated as tetravalent Nb-Fc fusion proteins for optimal CCR8 binding and blocking, containing either an ADCC-deficient or an ADCC-prone Fc region. While treatment of tumor-bearing mice with a blocking ADCC-deficient Nb-Fc did not influence tumor growth, ADCC-prone Nb-Fc elicited antitumor immunity and reduced tumor growth in synergy with anti-PD-1 therapy. Importantly, ADCC-prone Nb-Fc specifically depleted ti-Tregs without affecting peripheral Tregs. Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy.
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| Overall design |
Single cell RNA Seq = Live CD45+CD11b-TCRβ+ cells sorted from LLC-OVA tumors subcutaneously injected in WT C57BL/6 mice.
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| Contributor(s) |
Van Damme H, Laoui D, Movahedi K, Scheyltjens I, Vandamme N, Martens L, Kancheva D |
| Citation(s) |
33589525 |
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| Submission date |
Dec 03, 2020 |
| Last update date |
Feb 21, 2021 |
| Contact name |
Daliya Kancheva |
| E-mail(s) |
[email protected], [email protected]
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| Organization name |
Vrije Universiteit Brussel
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| Street address |
Pleinlaan 2
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| City |
Brussels |
| ZIP/Postal code |
1050 |
| Country |
Belgium |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (1) |
| GSM4955522 |
Live CD45+CD11b-TCRβ+ cells sorted from LLC-OVA tumors subcutaneously injected in WT C57BL/6 mice. |
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| Relations |
| BioProject |
PRJNA682411 |
| SRA |
SRP295690 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE162621_RAW.tar |
5.5 Mb |
(http)(custom) |
TAR (of CSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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