Academic Journal
Engineered human pluripotent stem cell-derived natural killer cells with PD-L1 responsive immunological memory for enhanced immunotherapeutic efficacy
| Title: | Engineered human pluripotent stem cell-derived natural killer cells with PD-L1 responsive immunological memory for enhanced immunotherapeutic efficacy |
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| Authors: | Yun Chang, Gyuhyung Jin, Weichuan Luo, Qian Luo, Juhyung Jung, Sydney N. Hummel, Sandra Torregrosa-Allen, Bennett D. Elzey, Philip S. Low, Xiaojun Lance Lian, Xiaoping Bao |
| Source: | Bioactive Materials, Vol 27, Iss , Pp 168-180 (2023) |
| Publisher Information: | KeAi Communications Co., Ltd., 2023. |
| Publication Year: | 2023 |
| Collection: | LCC:Materials of engineering and construction. Mechanics of materials LCC:Biology (General) |
| Subject Terms: | Natural killer cells, Human pluripotent stem cells, Immunological memory, Immunotherapy, Chimeric antigen receptor, Materials of engineering and construction. Mechanics of materials, TA401-492, Biology (General), QH301-705.5 |
| More Details: | Adoptive chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have shown promise in treating various cancers. However, limited immunological memory and access to sufficient numbers of allogenic donor cells have hindered their broader preclinical and clinical applications. Here, we first assess eight different CAR constructs that use an anti-PD-L1 nanobody and/or universal anti-fluorescein (FITC) single-chain variable fragment (scFv) to enhance antigen-specific proliferation and anti-tumor cytotoxicity of NK-92 cells against heterogenous solid tumors. We next genetically engineer human pluripotent stem cells (hPSCs) with optimized CARs and differentiate them into functional dual CAR-NK cells. The tumor microenvironment responsive anti-PD-L1 CAR effectively promoted hPSC-NK cell proliferation and cytotoxicity through antigen-dependent activation of phosphorylated STAT3 (pSTAT3) and pSTAT5 signaling pathways via an intracellular truncated IL-2 receptor β-chain (ΔIL-2Rβ) and STAT3-binding tyrosine-X-X-glutamine (YXXQ) motif. Anti-tumor activities of PD-L1-induced memory-like hPSC-NK cells were further boosted by administering a FITC-folate bi-specific adapter that bridges between a programmable anti-FITC CAR and folate receptor alpha-expressing breast tumor cells. Collectively, our hPSC CAR-NK engineering platform is modular and could constitute a realistic strategy to manufacture off-the-shelf CAR-NK cells with immunological memory-like phenotype for targeted immunotherapy. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2452-199X |
| Relation: | http://www.sciencedirect.com/science/article/pii/S2452199X23001123; https://doaj.org/toc/2452-199X |
| DOI: | 10.1016/j.bioactmat.2023.03.018 |
| Access URL: | https://doaj.org/article/132da242ecf24ecdaf6268b9a29f76ac |
| Accession Number: | edsdoj.132da242ecf24ecdaf6268b9a29f76ac |
| Database: | Directory of Open Access Journals |
| ISSN: | 2452199X |
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| DOI: | 10.1016/j.bioactmat.2023.03.018 |
| Published in: | Bioactive Materials |
| Language: | English |