Exosome-based Strategy

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Introduction

Exosome secretion levels are correlated with tumor stage and metastasis in the tumor microenvironment (TME). As signal molecules, exosomes contain selective repertoires of nucleic acids, proteins, lipids, and a series of metabolites. After their release into the extracellular environment, exosomes are taken up by recipient cells, both neighboring and distant, where they perform their regulatory functions. There is emerging evidence that tumor-derived exosomes (TEX) contribute to the recruitment and reprogramming of constituents associated with TME. Other cells in the TME also secrete exosomes. The two-way communication between tumor cells and the stroma or tumor can significantly affect the progression of disease and sensitivity of the tumor to treatment. Targeting exosomes could be a promising strategy in reshaping TME.

Fig.1 Biogenesis of exosomes. (Othman, 2019)

Exosomes in TME

Almost all cells can secrete exosomes. Exosomes derived from different cells exhibit different characteristics and functions. Cells in TME including cancer-associated fibroblasts (CAFs), cancer stem cells (CSCs), mesenchymal stromal cells (MSCs), tumor microenvironmental immune cells (TMICs), etc. use exosomes to transfer messages, contributing to tumor growth, epithelial-mesenchymal transition (EMT), tumor metastasis and drug resistance through a variety of mechanisms.

Fig.2 The roles of exosomes in tumors. (Osaki, 2019)

TEX can deliver multiple signals to surrounding cells and lay a pivotal role in tumor growth, angiogenesis and metastasis. TEX can

Help create an immunosuppressive TME by inhibiting the proliferative response of lymphocytes, inducing apoptosis, and impairing the function of effector T cells and NK cells, skewing dendritic cells (DCs) s differentiation into MDSCs as well as promoting Treg cell activity.
Promote epithelial to mesenchymal transition (EMT) and preparation of a premetastatic niche at the distant location.
Cause intratumor heterogeneity resulting from phenotype modification of normal cells after internalization of exosomes, such as the phenotype shift of macrophages to tumor-associated macrophages (TAM), and the differentiation of fibroblasts into CAF.

Exosomes derived from nontumor cells also can influence the TME.

CAF-derived exosomes are one of the key factors of oncogenic transformation. CAF-derived exosomes promote the growth of tumor cells by increasing glycolysis and glutamine-dependent reduction carboxylation in tumor cells and promote drug resistance and tumor metastasis.
MSC-derived exosomes upregulate MMP-2 and activate ecto-5'-nucleases, causing tumor cells to become more malignant and thus altering the TME, as well as enhancing tumor heterogeneity.
Exosomes from healthy cells including dendritic cells, B cells, and T cells, play a crucial immune role in inhibiting tumor growth.
Dendritic cells (DCs) could promote CTL generation, while Treg-cell-derived exosomes could inhibit CTL generation.

Application of Exosomes

Exosomes, and the genetic material and proteins that they contain, have shown promise as useful indicators of tumor burden, and prognosis, and perhaps even as a therapeutic treatment, as they modulate so many aspects of heterotypic cell-cell interaction in the TME. Currently, several different methods have been developed for tumor therapies: (1) using naturally-derived exosomes from immune cells to suppress tumor cells; (2) inhibiting the release of tumor; (3) using exosomes as gene carriers; and (4) using exosomes as anti-tumor drug carriers; 5) exosomes derived from specific sites in the body can be promising candidates for anti-tumor vaccines since they can present antigens against that specific type of tumors.

Exosomal drug delivery system with minimal toxicity, biocompatibility, tissue and tumor targeting, and long-circulating half-life emerges to be a superior choice. Therapeutic and targeted delivery at the tumor site can be achieved by modifying exosomes with corresponding targeting ligands. By engineering the parent cells to secrete modified exosomes, or alternatively, directly manipulating exosome content following secretion, exosomes are utilized for the therapeutic delivery of small molecules, proteins, and RNAs. Exosomes derived from specific sites in the body can be promising candidates for anti-tumor vaccines since they can present antigens against that specific type of tumor. DC-derived exosomes, containing MHC I, MHC II, CD86, and HSP70-90 chaperones, can trigger CD4⁺ and CD8⁺ T cell activation. TEXs express and transfer a wide spectrum of tumor-associated antigens to DCs that can prime tumor-specific cytotoxic T lymphocytes and induce potent antitumor immunity. Despite exerting remarkable vaccination effects, TEXs also display pro-tumorigenic characteristics as they resemble their original tumor cells. In particular, for the therapeutic application of exosomes, the source of exosomes needs to be carefully considered.

Fig.3 Manipulation of exosomes to carry next-generation chemotherapeutic drugs, modified DNA, RNA, peptides to the tumor cells. (Dutta, 2021)

Creative Biolabs is dedicated to offering comprehensive exosome-related products and services including drug loading into exosomes and exosome genetic modification. Please feel free to contact us if you are interested in our services.

References

Othman, N.; et al. Cancer-derived exosomes as effectors of key inflammation-related players. Frontiers in immunology. 2019, 10: 2103.
Osaki, M.; Okada, F. Exosomes and their role in cancer progression. Yonago acta medica. 2019, 62(2): 182-190.
Dutta, A. Exosomes-based cell-free cancer therapy: A novel strategy for targeted therapy. Immunological Medicine. 2021, 44(2): 116-123.