Extracellular vesicles in immunomodulation and tumor progression

Abstract

Extracellular vesicles have emerged as prominent regulators of the immune response during tumor progression. EVs contain a diverse repertoire of molecular cargo that plays a critical role in immunomodulation. Here, we identify the role of EVs as mediators of communication between cancer and immune cells. This expanded role of EVs may shed light on the mechanisms behind tumor progression and provide translational diagnostic and prognostic tools for immunologists.

Figure 1:. Heterogeneous cargo of EVs.

Secreted from tumor and immune cells alike, EVs contain molecular cargo that facilitates immune stimulatory and suppressive interactions. Trafficking transmembrane and cytosolic proteins, RNAs, and DNAs, EVs regulate autoimmune and disease responses. A) EVs secreted by immune cells carry cargo that directly controls peripheral immune function by either promoting a regulatory response or conditioning surrounding cells, reducing inflammation. B) Tumor-derived EVs express surface and cytosolic markers from their cellular progenitor, which in turn induce phenotypic changes in recipient cells.

Figure 2:. Mechanisms of EV immune regulation.

EVs released by immune cells constantly balance immune regulatory and autoimmune responses of surrounding cells in a highly interwoven network of immune responses. EVs promote cell maturation, polarization, and differentiation in T cells and mononuclear cells. Encapsulation and stabilization of EV-associated cytokines further extend the functional capacity of immune EVs by regulating cytokine release and downstream proliferation.

Figure 3:. Cancer EVs directly regulate tumor progression.

A) EVs released by cancer cells promote tumor progression through the suppression of adaptive and innate immune cells. Impeding effective antigen cross presentation in dendritic cells, EVs also contribute to T cell dysfunction through check point inhibition. Additionally, cancer EVs polarize mononuclear cells towards an immunosuppressive phenotype, while reducing cytotoxicity in NK cells. Less restricted by physical constraints, cancer EVs demonstrate far reaching immunosuppressive effects on circulatory and distal immune cells. B) Cancer EVs function as vessels for tumor recognition. During a functional immune response, EVs deliver foreign antigens to dendritic cells indirectly stimulating cytotoxic T cells. While macrophages actively sequester cancer EVs from circulation promoting cancer cell recognition. Molecules highlighted in red stimulate immune activation; molecules highlighted in black describe immunosuppressive cargo.

Figure 4:. Potential clinical translations for EVs.

EVs have emerged as powerful tools for cancer treatment. Synthetic and re-appropriated natural EVs carry bioactive molecules that enhance the immunological roles of EVs, indicate disease prognosis, or facilitate drug delivery to the tumor site. These capacities are the focus of several ongoing clinical trials.