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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Aug 11, 2022 |
| Title |
Efficacious anti-CTLA-4 antibodies drive myeloid activation and TME reprograming through FcγR engagement and Type-I interferon signaling |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Despite the clinical success of checkpoints inhibitors, a significant gap still exists in our understanding of their in vivo mechanism of action, thus limiting the rational development of next generation agents. Amongst these, anti-CTLA-4 antibodies were originally developed to block inhibitory signals into activated effector T cells. However, several recent studies have demonstrated that depletion of regulatory T cells expressing high levels of CTLA-4 is critical to anti-CTLA-4 anti-tumor activity. Whereas the mechanism of action remains controversial, the emerging data support clinical development of new antibodies with enhanced killing activity. Here, using single-cell RNA sequencing in in vivo and in vitro mouse models, we sought to dissect the impact of anti-CTLA-4 blocking, Treg depleting, and FcR engaging activity on the immune responses within tumors. We observed a rapid remodeling of the innate immune landscape as early as 24-hours post-treatment. Immune remodeling was driven mainly by FcγR-engagement, and not by Treg depletion or CTLA-4 blockade, and included reduction of suppressive macrophages and activation of type-I interferon signaling. Our findings indicate that FcγR engagement and innate immune remodeling are involved in successful anti-CTLA-4 treatment, supporting further development of optimized immunotherapy agents with these features.
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| Overall design |
Dissecting the effect of blocking vs depleting anti-CTLA4 mAb on tumor immune microenvironment using single-cell RNA sequencing. Mice were inoculated with MCA-205 cells and treated with either Anti-CTLA-4 mIgG1 or Anti-CTLA-4 mIgG2a or untreated. Immune cells were harvested from tumors in 2 different time-points and underwent scRNAseq. We also utilized FOXP3-DTR, IFNAR KO and FCGR KO mice in different settings. Ex vivo incubation of iTregs with bone-marrow derived myeloid cells was performed.
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| Contributor(s) |
Yofe I, Landsberger T, Yalin A, Solomon I, Costoya C, Franz-Demane D, David E, Borenstein C, Garcia IM, Peggs KS, Quezada SA, Amit I |
| Citation(s) |
36302895 |
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| Submission date |
Oct 24, 2021 |
| Last update date |
Nov 09, 2022 |
| Contact name |
Ido Amit |
| E-mail(s) |
ido.amit@weizmann.ac.il
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| Phone |
972-8-9343338
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| Organization name |
Weizmann Institute of Science
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| Department |
Immunology
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| Street address |
234 Herzl st.
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| City |
Rehovot |
| ZIP/Postal code |
760001 |
| Country |
Israel |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (368)
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| Relations |
| BioProject |
PRJNA774055 |
| SRA |
SRP342910 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE186484_M_metadata_r.txt.gz |
2.4 Mb |
(ftp)(http) |
TXT |
| GSE186484_RAW.tar |
324.9 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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