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| Status |
Public on Sep 29, 2023 |
| Title |
The Second Generation of CAR-iMACs with Enhanced Polarization, CAR-mediated Efferocytosis and Superior Potency against Solid Tumors |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Chimeric antigen receptor (CAR)-T cell therapies have shown great success in treating hematologic malignancies. Nonetheless, their therapeutic effect on solid tumors remains to be improved. Recently, macrophages have attracted great attention, given their ability to infiltrate solid tumors, phagocytize tumor cells as well as their immunomodulatory capacities. The first generation of CD3ζ-based CAR-macrophages demonstrated that the CAR could stimulate macrophage phagocytosis in a tumor antigen-dependent way. Here, we genetically engineered induced pluripotent stem cell (iPSC)-derived macrophages (iMACs) with TLR4 intracellular TIR domain-containing CARs against EGFRvIII and GPC3, which yielded markedly enhanced antitumor effect in two different solid tumor models including glioblastoma, and hepatocellular carcinoma in which complete remission was achieved with CAR-iMACs alone or in combination with CD47 antibody. Moreover, the tandem CD3ζ-TIR-CAR, or the “second-generation” design of TIR-based dual signaling CAR, endowed iMACs with both target engulfment/efferocytosis capacity against antigen-expressing solid tumor cells, and potency of antigen-dependent M1 state polarization and M2 state resistance in an NF-κB dependent manner. We also illustrated a surprising mechanism of tumor cell elimination by CAR-induced efferocytosis against tumor cell apoptotic bodies. Taken together, we established the next generation CAR-iMACs equipped with orthogonal phagocytosis and polarization capacity for better antitumor functions in treating solid tumors.
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| Overall design |
We pretreated EGFRvIII-targeting CAR-iMACs were incubated with U87MGEGFRvIII cells with IFN-γ/LPS for 24 hours. Subsequently, we performed 10×genomics single-cell RNA-sequencing and found that TIR-based CARs contributed to the proinflammatory state of CAR-iMACs in a CAR- and antigen-dependent manner when encountering tumor cells and improved immune activity against target tumor cells.
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| Contributor(s) |
Lei A, Yu H, Zhu Y |
| Citation missing |
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| Submission date |
Sep 25, 2022 |
| Last update date |
Sep 30, 2023 |
| Contact name |
Hua Yu |
| E-mail(s) |
yuhua@westlake.edu.cn
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| Phone |
18758008246
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| Organization name |
Westlake University
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| Street address |
No.18 Shilongshan Road
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| City |
Hangzhou |
| ZIP/Postal code |
310024 |
| Country |
China |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (3) |
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| Relations |
| BioProject |
PRJNA884115 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE214140_RAW.tar |
259.2 Mb |
(http)(custom) |
TAR (of TAR) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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