Journal
THERANOSTICS
Volume 11, Issue 12, Pages 6033-6043Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.48868
Keywords
Cancer immunotherapy; checkpoint antibody; CD64; Regulatory T cells; Nanovesicle
Categories
Funding
- National Natural Science Foundation of China [31971268]
- Natural Science Foundation of Guangdong Province [2020A1515010802]
- Guangdong Basic and Applied Basic Research Foundation [2019A1515010855, 2019A1515110395, 2020A1515110166]
- Shenzhen Excellent Science and Technology Innovation Talent Training Project (Excellent Youth Project) [RCYX 20200714114643121]
- Basic Research Program of Shenzhen [JCYJ20200109142610136, JCYJ20180507183428877, JCYJ20170818162637217, JCYJ20180507181654186]
- Health system scientific research project of Shenzhen Guangming District Science and innovation Bureau [2020R01073, 2020R01061]
- University of Chinese Academy of Sciences-Shenzhen Hospital Research Funding [HRF-2020004]
- Fundamental Research Funds for the Central Universities [19lgzd45]
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By overexpressing CD64 on cell membrane nanovesicles and encapsulating PD-L1 antibody and chemotherapeutic agent CP, the CD64-NVs-aPD-L1-CP can simultaneously disrupt the immunosuppressive effect of PD-L1, decrease the inhibition of Tregs, enhance the tumor elimination by T cells, suppress tumor growth, and extend survival time, making them charismatic carriers for combined cancer immunotherapy.
Immune checkpoint blockade therapies, especially those targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) have achieved impressive clinical responses in multiple types of cancers. To optimize the therapeutic effect of the checkpoint antibodies, many strategies including targeting delivery, controlled release, and cellular synthesis have been developed. However, within these strategies, antibodies were attached to drug carriers by chemical bonding, which may affect the steric configuration and function of the antibodies. Herein, we prepared cluster of differentiation 64 (CD64), a natural catcher of the fragment crystalline (Fc) of monomeric immunoglobulin G (IgG), and over-expressed it on the cell membrane nanovesicles (NVs) as PD-L1 antibody delivery vehicle (CD64-NVs-aPD-L1), which was employed to disrupt the PD-1/PD-L1 immunosuppressive signal axis for boosting T cell dependent tumor elimination. Meanwhile, chemical immunomodulatory drug cyclophosphamide (CP) was also encapsulated in the vesicle (CD64-NVs-aPD-L1-CP), to simultaneously restrain the regulatory T cells (Tregs) and invigorate Ki67(+)CD8(+) T cells, then further enhance their anti-tumor ability. Methods: The cell membrane NVs overexpressing CD64 were incubated with PD-L1 antibody and chemotherapeutic agent CP to prepare CD64-NVs-aPD-L1-CP. Results: The CD64-NVs-aPD-L1-CP could simultaneously interrupt the immunosuppressive effect of PD-L1 and decrease the inhibition of Tregs, leading to tumor growth suppression and survival time extension. Conclusion: CD64-NVs are charismatic carriers to achieve both checkpoint blockade and immunomodulatory drugs for combined cancer immunotherapy.
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