Abscopal Effect, Extracellular Vesicles and Their Immunotherapeutic Potential in Cancer Treatment

Abstract

The communication between tumor cells and the microenvironment plays a fundamental role in the development, growth and further immune escape of the tumor. This communication is partially regulated by extracellular vesicles which can direct the behavior of surrounding cells. In recent years, it has been proposed that this feature could be applied as a potential treatment against cancer, since several studies have shown that tumors treated with radiotherapy can elicit a strong enough immune response to eliminate distant metastasis; this phenomenon is called the abscopal effect. The mechanism behind this effect may include the release of extracellular vesicles loaded with damage-associated molecular patterns and tumor-derived antigens which activates an antigen-specific immune response. This review will focus on the recent discoveries in cancer cell communications via extracellular vesicles and their implication in tumor development, as well as their potential use as an immunotherapeutic treatment against cancer.

Keywords: DAMPs; abscopal effect; cancer; extracellular vesicles.

Figure 1

Effects of tumor-derived EV content on non-cancer cells. Tumor cells can release EVs loaded with miRNAs, LncRNA, cytokines, growth factors and immune checkpoint molecules, as well as death receptors and their ligands; the content of the EVs will differentially affect the tumor microenvironment by affecting immune, endothelial and mesenchymal cells within the tumor, promoting the activation of several pathways leading to immune escape and tumor progression.

Figure 2

DC activation via extracellular vesicles. DC activation can be enhanced via the modification of tumor-derived EVs containing TAA and NA via several mechanisms: first, by coating the EVs with molecules such as sialic acid or CD40L to promote the uptake of EVs; second, via the loading of miRNAs related to activation and antigen processing, such as Let-7i, miR-155 and miR-142; third, via the codelivery of PAMPs in the EVs, such as ESAT-6 and CpG-DNA; and fourth, via the codelivery of DAMPs in the EVs after the irradiation of tumor cells, leading to increased EV phagocytosis, DC activation and maturation, antigen processing and cross-presentation and the expression of MHC class I and MHC class II molecules and costimulatory molecules such as CD80 and CD86.

Figure 3

TAM reprograming via extracellular vesicles. EVs can be modified to reprogram M2-TAMs to M1-TAMs, independently of their cell origin. Irradiated tumor-cell-derived EVs loaded with damage-associated molecular patterns (DAMPs), tumor-associated antigens (TAAs) and neoantigens (NAs) induce the M1 polarization of TAMs. EVs loaded with Gal9-siRNA and oxaliplatin (OX) inhibit the expression of Gal9 in tumor cells, blocking the activation of dectin-1 on macrophages and inducing the M2 phenotype via immunogenic cell death. EVs loaded with STAT6-ASO inhibit M2 polarization by inducing STAT1. EVs coated with mannose promote their uptake via CD206-expressing M2 macrophages and induce M1 phenotype via the delivery of metformin, via the activation of NFκB. The “don’t eat me” signal by the CD47-SIRPα axis can be blocked with EVs expressing SIRPα and by EVs conjugated with anti-CD47 and anti-SIRPα antibodies, promoting phagocytosis, the synthesis of iNOS, IL-1, IL-6, IL-12, TNF-α and IFN-γ and the expression of CD80/CD86 molecules.

Figure 4

Stimulation of T cell response via extracellular vesicles and their interplay with immune checkpoint inhibition. T cell activation is enhanced via the inhibition of the PD-1-PD-L1 axis by several mechanisms. Among these are the downregulation of PD-L1 by EVs loaded with PD-L1-siRNA in tumor cells, the blockade of PD-L1 via the anti-PD-L1 antibody coupled to CD64-expressing EVs, the blockade of PD-L1 on tumor cells by Gram negative bacteria (GNB)-derived EVs expressing PD-1, and the blockade of PD-L1 via the delivery of activated T-cell-derived EVs overexpressing PD-1. Additionally, irradiated or heated tumor-cell-derived EVs effectively induce a memory T cell response. CAR-T-cell-derived EVs maintain cytotoxic activity.