Engineered Removal of PD-1 From the Surface of CD19 CAR-T Cells Results in Increased Activation and Diminished Survival
| Autor: | Michael Maschan, S. P. Chumakov, D. V. Volkov, Yury P. Rubtsov, Alexey Stepanov, A. M. Moysenovich, Eugene G. Maksimov, Dmitry Pershin, R. S. Kalinin, V. M. Tereshchuk, Hongkai Zhang, V. M. Ukrainskaya |
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| Rok vydání: | 2021 |
| Předmět: |
PD-L1
QH301-705.5 Biochemistry Genetics and Molecular Biology (miscellaneous) Biochemistry CD19 Cell therapy Immune system TIGIT Downregulation and upregulation PD-1 medicine tumor microenvironment Cytotoxic T cell Molecular Biosciences Biology (General) Molecular Biology B cell Original Research CAR T cells Tumor microenvironment protein expression blockers biology Chemistry medicine.anatomical_structure Cancer research biology.protein human activities |
| Zdroj: | Frontiers in Molecular Biosciences Frontiers in Molecular Biosciences, Vol 8 (2021) |
| ISSN: | 2296-889X |
| Popis: | CAR-T cell therapy is the most advanced way to treat therapy resistant hematologic cancers, in particular B cell lymphomas and leukemias, with high efficiency. Donor T cells equipped ex vivo with chimeric receptor recognize target tumor cells and kill them using lytic granules. CAR-T cells that recognize CD19 marker of B cells (CD19 CAR-T) are considered the gold standard of CAR-T therapy and are approved by FDA. But in some cases, CD19 CAR-T cell therapy fails due to immune suppressive microenvironment. It is shown that tumor cells upregulate expression of PD-L1 surface molecule that binds and increases level and signal provided by PD-1 receptor on the surface of therapeutic CAR-T cells. Induction of this negative signaling results in functional impairment of cytotoxic program in CAR-T cells. Multiple attempts were made to block PD-1 signaling by reducing binding or surface level of PD-1 in CAR-T cells by various means. In this study we co-expressed CD19-CAR with PD-1-specific VHH domain of anti-PD-1 nanobody to block PD-1/PD-L1 signaling in CD19 CAR-T cells. Unexpectedly, despite increased activation of CAR-T cells with low level of PD-1, these T cells had reduced survival and diminished cytotoxicity. Functional impairment caused by disrupted PD-1 signaling was accompanied by faster maturation and upregulation of exhaustion marker TIGIT in CAR-T cells. We conclude that PD-1 in addition to its direct negative effect on CAR-induced signaling is required for attenuation of strong stimulation leading to cell death and functional exhaustion. These observations suggest that PD-1 downregulation should not be considered as the way to improve the quality of therapeutic CAR-T cells. |
| Databáze: | OpenAIRE |
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