# Crosstalk of Tumor-Derived Extracellular Vesicles with Immune Recipient Cells and Cancer Metastasis

## TL;DR

Tumor-derived extracellular vesicles (TEX) alter immune cell function, promoting cancer metastasis by reprogramming immune cells from anti-tumor to pro-tumor activity.

## Contribution

The study reveals that TEX use HSP-90/TLR2 signaling to activate immune pathways, leading to macrophage polarization and T-cell apoptosis.

## Key findings

- TEX activate NF-κB and MAP kinase pathways in THP-1 cells, promoting polarization to TAMs.
- Melanoma-derived TEX induce mitochondrial stress and apoptosis in T-cells via DAMP signaling.
- TEX are equipped by tumors to engage immune cell PRRs, mimicking pathogens to alter immune responses.

## Abstract

The involvement of tumor-derived extracellular vesicles, TEX, in tumor progression and metastasis includes their crosstalk with various immune cells in the TME. An in vitro model of THP-1 myeloid cells co-incubated with TEX illustrates the role TEX play in polarization of macrophages to TAMs. TEX acting like DAMPs initiate the HSP-90/TLR2 axis signaling in THP-1 cells, activating the NF-κB and MAP kinase pathways and driving THP-1 cell polarization. This process of metabolic reprogramming of the immune cells from anti-tumor to pro-tumor activity promotes metastasis development.

Background. Contributions of tumor-derived extracellular vesicles, TEX, to tumor progression and metastasis involve their crosstalk with immune cells in the tumor microenvironment. This crosstalk results in metabolic reprogramming of immune cells from anti-tumor to pro-tumor activity. Mechanistic underpinnings of the TEX entry and delivery of molecular signals responsible for metabolic reprogramming may be unique for different types of immune cells. Methods. An in vitro model of THP-1 myeloid cells co-incubated with TEX illustrates the role TEX play in polarization of macrophages to TAMs. Results. In THP-1 cells, the dominant signaling pathway of melanoma cell-derived TEX involves HSP-90/TLR2. This leads to activation of the NF-κB and MAP kinase pathways and initiates THP-1 cell polarization from M0 to M2 with strong expression of immunosuppressive PD-L1. TEX may be seen as “danger” by the myeloid cells, which utilize the pattern recognition receptors (PRR), such as PAMPs or DAMPs, for engaging the complementary ligands carried by TEX. The same melanoma TEX signaling to T cells via DAMPs induced mitochondrial stress, resulting in T-cell apoptosis. Conclusions. As the signaling receptors/ligands in TEX are determined by the tumor, it appears that the tumor equips TEX with an address recognizing specific PRRs expressed on different recipient immune cells. Thus, TEX, acting like pathogens, are equipped by the tumor to alter the context of intercellular crosstalk and impose a distinct autophagy-not-apoptosis signature in recipient THP-1 cells. The tumor might endorse TEX to promote tumor progression and metastasis by enabling them to engage the signaling system normally used by immune cells for defense against pathogens.