Extracellular Vesicles and Endogenous Retroviruses Impact Dendritic Cells

Core Concepts

The author explores the impact of tumor-derived extracellular vesicles (EVs) containing endogenous retroviruses on dendritic cells, highlighting distinct functions and immunogenicity of different EV subtypes.

Abstract

The study investigates the diverse effects of tumor-derived EVs on dendritic cells, revealing a novel subtype of small EVs containing virus-like particles. These VLPs induce immune activation and cross-presentation, contrasting with sEVs that cause cell death. The 10k fraction emerges as the most immunogenic, promoting DC maturation and cytokine secretion. Proteomic analysis uncovers specific proteins associated with each EV subtype, shedding light on their distinct functional roles. Cells secrete membrane-enclosed extracellular vesicles (EVs) and non-vesicular nanoparticles (ENPs) that play a role in intercellular communication. Tumor-derived EVs have been proposed to either induce immune priming or promote immune escape. The study aims to characterize secreted EVs and ENPs from murine tumor cell lines to understand their impact on dendritic cells (DCs). Unexpectedly, virus-like particles (VLPs) from endogenous murine leukemia virus are identified in tumor cell-derived EV preparations. The research establishes a protocol to separate small EVs from VLPs and ENPs, comparing their protein composition and functional interaction with target DCs. While ENPs show poor capture ability without affecting DCs, sEVs induce DC death. A mixed preparation of EV/VLP is most efficient in inducing DC maturation and antigen presentation. These findings suggest a need for re-evaluation of non-viral EV proportions in tumors' contribution to anti-tumor immune responses. Intercellular communication is vital in tissues like the tumor microenvironment where cancer cells influence stromal and immune cells through soluble factors, extracellular vesicles (EVs), and other nanoparticles. Novel technologies have revealed heterogeneity in these particles but little is known about their biological functions. Viral infection adds complexity to the secretome as viruses utilize host processes for survival, modifying the composition of released EVs. Endogenous retroviruses represent potential sources of viral particles within EV preparations from tumors. The study highlights distinct functions of different subtypes of tumor-derived particles on DC maturation, antigen presentation, and immune activation. Proteomic analysis reveals specific proteins associated with each particle subtype that may contribute to their differential effects on target cells.

Stats

Nanoparticle tracking analysis showed varying sizes among different fractions. Cryo-electron microscopy revealed virus-like particles within certain fractions. Western blot detected viral proteins specifically in VLP-containing fractions. Quantitative proteomic analysis identified unique protein profiles for each particle subtype.

Quotes

"Unexpectedly, we identified virus-like particles (VLPs) from endogenous murine leukemia virus in preparations of EVs produced by tumor cells." "Our results unravel a limited potential of VLP-devoid small EVs for the induction of antigen-specific immune responses."

Key Insights Distilled From

Extracellular vesicles and co-isolated endogenous retroviruses differently affect dendritic cells

by Cocozza,F., ... at www.biorxiv.org 01-28-2023

https://www.biorxiv.org/content/10.1101/2023.01.27.525863v1

Deeper Inquiries

What implications do these findings have for understanding the role of endogenous retroviruses in cancer progression?

The presence of virus-like particles (VLPs) and infectious retroviral particles in tumor-derived extracellular vesicles (EVs) sheds light on the potential involvement of endogenous retroviruses (ERVs) in cancer progression. These findings suggest that ERVs, which are normally dormant or non-infectious, can be reactivated within tumor cells to produce VLPs with infectivity. This activation may contribute to immune responses and potentially impact the tumor microenvironment. Understanding how ERVs can be mobilized by tumors to produce infectious viral particles provides insights into a novel mechanism through which viruses may influence cancer development and progression.

How might the presence of VLP-containing small EV subtypes impact current strategies for utilizing tumor-derived extracellular vesicles?

The identification of VLP-containing small EV subtypes among tumor-derived EV preparations has significant implications for current strategies involving the use of extracellular vesicles in cancer research and therapy. Firstly, it highlights the importance of characterizing EV subpopulations to understand their diverse functions accurately. Incorporating this knowledge into existing methodologies for isolating and analyzing EVs from tumors could lead to more targeted approaches based on specific subtypes' properties. Moreover, considering the distinct effects observed between sEVs and VLPs on dendritic cells (DCs), future studies focusing on harnessing these different particle types could provide new avenues for therapeutic interventions. By leveraging the immunogenic potential of VLP-containing EV fractions while mitigating any toxic effects associated with other subtypes like sEVs, researchers may develop more precise treatment modalities using engineered or purified EV populations tailored towards desired outcomes.

In what ways could exploring the distinct functions of various particle subtypes lead to novel therapeutic approaches beyond immunotherapy?

Exploring the distinct functions of different particle subtypes within tumor-derived extracellular vesicles opens up possibilities for novel therapeutic approaches beyond traditional immunotherapy methods: Targeted Drug Delivery: By understanding how specific particle types interact with target cells differently, researchers can design drug-loaded EV formulations that selectively deliver therapeutics based on desired cellular responses. Diagnostic Biomarkers: Characterizing unique protein signatures or cargo contents associated with each subtype enables the development of diagnostic biomarkers derived from circulating EV populations indicative of disease states or treatment responses. Gene Therapy Vehicles: Utilizing engineered exosomes enriched with beneficial cargo carried by certain particle subsets offers a promising avenue for gene therapy delivery systems capable of modulating genetic expression profiles in target tissues. Combination Therapies: Combining multiple purified EV fractions targeting different pathways simultaneously could enhance treatment efficacy by exploiting synergistic effects while minimizing adverse reactions associated with single-agent therapies. Overall, delving deeper into understanding how diverse particle subpopulations function within tumor-derived extracellular vesicles paves the way for innovative therapeutic strategies that leverage these natural nanocarriers' capabilities effectively across various medical applications beyond conventional immunotherapies alone.