DC-Derived Exosomes for Cancer Immunotherapy
<p>Biogenesis and characteristics of exosomes. Exosomes are produced in the endosomal compartment by inward budding of limiting endosomal membrane into intraluminal vesicles (ILVs) within the lumen of multivesicular bodies (MVBs). MVBs are either targeted for lysosomal degradation or they may fuse with plasma membrane to release these ILVs into the extracellular space as free exosomes. Exosomes are highly heterogenous with size ranging from 40 to 160 nm. Besides expressing an array of receptors on their surface, exosomes carry proteins, metabolites and nucleic acids including mRNA, miRNA, other non-coding RNA and DNA. Tetraspanins (CD9, CD63 and CD81) and other proteins such as Alix and TSG101 are often enriched in exosomes, and are commonly used as markers for exosomes.</p> "> Figure 2
<p>DCexo-mediated antigen presentation to activate T cells. (<b>A</b>): The presence of MHC<sub>Exo</sub>-Ag complexes on the surface of DCexos enables them to activate antigen-specific CD4 and CD8 T cells directly. Only MHCI and CD8 T cells are illustrated. NK cell-expressed ligands (NKG2D-L, IL-15R and BAG6) on DCexos can also activate natural killer (NK) cells directly. (<b>B</b>–<b>C</b>): DCexos activate antigen-specific T cells more efficiently indirectly via bystander DCs. (<b>B</b>): DCexos can transfer MHC<sub>Exo</sub>-Ag complexes to the DC plasma membrane, a process termed cross-dressing, leading to activation of antigen-specific T cells. MHC of DCexos and T cells has to be the same while MHC of the bystander DCs is not required. DCexos can also transfer MHC<sub>Exo</sub>-Ag complexes to tumor cells to be presented to host T cells (not depicted). (<b>C</b>): After internalization, (<b>C-1</b>) DCexos could transfer antigenic peptides to the MHC<sub>DC</sub> in bystander DCs. The pMHC<sub>DC</sub> complexes could be transported to the DC plasma membrane to be presented to T cells. DCexos, bystander DCs and T cells are required to have the same MHC in this mode. (<b>C-2</b>) Protein antigens carried by DCexos could be processed by bystander DCs, and multiple and different epitopes for both CD4 and CD8 T cells could be presented on MHC of bystander DCs. Only bystander DCs and T cells need to have the same MHC, allowing DCexos to induce allogeneic T cell responses.</p> "> Figure 3
<p>Exosome-based mRNA vaccines for immunotherapy. Combining exosome and mRNA vaccines might represent a promising strategy to further improve mRNA-based vaccines again infectious diseases and cancer: receptors on exosomes could enhance the targeted delivery of mRNAs, and multiple mRNAs could be efficiently delivered.</p> ">
Abstract
:Simple Summary
Abstract
1. Dendritic Cells, Anti-Tumor Immunity and Dendritic Cell-Based Cancer Vaccines
2. DC-Derived Exosomes and Their Function
3. DC-Derived Exosomes in Clinical Trials
4. DCexo Phase I Clinical Trials
5. DCexo Phase II Clinical Trial
6. Conclusions and Future Directions
7. Plasmacytoid DC-Derived Exosomes—The New Addition to DCexos
8. The Future of DCexos as Cancer Vaccines?
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Cancer Type | Phase | Exosomes /Antigen | Doses | Patients | Toxicity | Clinical Outcomes |
---|---|---|---|---|---|---|
Advanced Non-small cell lung cancer | I | Exosomes were isolated from autologous MoDCs generated in vitro, and loaded with MAGE peptides | once weekly for 4 weeks | 13 (9 completed) HLA-A2+ stage IIIb and IV NSCLC patients with tumor expression of MAGE3 or MAGE4 | Grade 1–2 toxicity | DTH reactivity against MAGE peptides in 3/9; MAGE-specific T cell responses in 1/3 patients examined; increased NK lytic activity in 2/4 [79]. |
MAGE3- expressing advanced melanoma | I | Autologous MoDC-derived exosomes were loaded with MAGE3 peptides | once weekly for 4 weeks | 15 stage IIIb and IV, HLA-A1+, B35+ or HLA-DPO4+ patients | Only grade 1 toxicity | No detectable MAGE3-specific CD4 and CD8 T cell responses; restored NKG2D expression and NKG2D-dependent function of NK cells in 7/14 patients; 1/15 partial responses [67,80]. |
Advanced colorectal cancer | I | Exosomes from patient ascites + GM-CSF, ASexos contained CEA with no additional antigen loading. | once weekly for 4 weeks | 40 HLA-A2+CEA+ stage III and IV CRC patients | Grade 1–2 toxicity | DTH induction in both groups, and CEA-specific CTL responses were observed in ASexo + GM-CSF group. 1 stable disease and 1 minor response in ASexo + GM-CSF group [82]. |
Non-small cell lung cancer | II | IFN-γ-matured autologous MoDCs were loaded with both MHCI and MHCII tumor epitopes. | exosome immunization in 1, 2 and 3 week intervals in a maintenance immunotherapy regime | 26 (22 HLA-A2+ stage IIIb and IV NSCLC patients | 1/22 grade 3 hepato-toxicity | No detectable induction of antigen-specific T cell responses; increased NKp30-dependent NK cell function; 7 patients (32%) with progression-free survival at 4 months after chemotherapy cessation; no objective tumor response according to RECIST criteria [81]. |
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Yao, Y.; Fu, C.; Zhou, L.; Mi, Q.-S.; Jiang, A. DC-Derived Exosomes for Cancer Immunotherapy. Cancers 2021, 13, 3667. https://doi.org/10.3390/cancers13153667
Yao Y, Fu C, Zhou L, Mi Q-S, Jiang A. DC-Derived Exosomes for Cancer Immunotherapy. Cancers. 2021; 13(15):3667. https://doi.org/10.3390/cancers13153667
Chicago/Turabian StyleYao, Yi, Chunmei Fu, Li Zhou, Qing-Sheng Mi, and Aimin Jiang. 2021. "DC-Derived Exosomes for Cancer Immunotherapy" Cancers 13, no. 15: 3667. https://doi.org/10.3390/cancers13153667
APA StyleYao, Y., Fu, C., Zhou, L., Mi, Q. -S., & Jiang, A. (2021). DC-Derived Exosomes for Cancer Immunotherapy. Cancers, 13(15), 3667. https://doi.org/10.3390/cancers13153667