Immunotherapy Based on Dendritic Cell-Targeted/-Derived Extracellular Vesicles—A Novel Strategy for Enhancement of the Anti-tumor Immune Response

Abstract

Dendritic cell (DC)-based anti-tumor vaccines have great potential for the treatment of cancer. To date, a large number of clinical trials involving DC-based vaccines have been conducted with a view to treating tumors of different histological origins. However, DC-based vaccines had several drawbacks, including problems with targeted delivery of tumor antigens to DCs and prolong storage of cellular vaccines. Therefore, the development of other immunotherapeutic approaches capable of enhancing the immunogenicity of existing DC-based vaccines or directly triggering anti-tumor immune responses is of great interest. Extracellular vesicles (EVs) are released by almost all types of eukaryotic cells for paracrine signaling. EVs can interact with target cells and change their functional activity by delivering different signaling molecules including mRNA, non-coding RNA, proteins, and lipids. EVs have potential benefits as natural vectors for the delivery of RNA and other therapeutic molecules targeted to DCs, T-lymphocytes, and tumor cells; therefore, EVs are a promising entity for the development of novel cell-free anti-tumor vaccines that may be a favourable alternative to DC-based vaccines. In the present review, we discuss the anti-tumor potential of EVs derived from DCs, tumors, and other cells. Methods of EV isolation are systematized, and key molecules carried by EVs that are necessary for the activation of a DC-mediated anti-tumor immune response are analyzed with a focus on the RNA component of EVs. Characteristics of anti-tumor immune responses induced by EVs in vitro and in vivo are reviewed. Finally, perspectives and challenges with the use of EVs for the development of anti-tumor cell-free vaccines are considered.

Extracellular Vesicles as Biomarkers in Cancer Immunotherapy

“…For example, DCs act in the first step of the cancer immunity cycle, eliminating tumor cells through T-cell activation [ 79 ]. As they share surface membrane components that interact with other immune cells, DC-derived EVs can potentially be engineered to act as cell-free antitumor vaccines, providing a novel immunotherapy in the fight against cancer [ 80 ]. Particularly, EVs released by DCs contain major histocompatibility complex (MHC) class I and class II molecules that are able to activate cognate T cells and promote humoral responses.…”

Extracellular Vesicles After Allogeneic Hematopoietic Cell Transplantation: Emerging Role in Post-Transplant Complications

“…In addition to NK-EVs, the anti-tumor effect of DCderived EVs (DC-EVs) for immunotherapy of cancer is under investigation in clinical trials (110). DCs are professional APCs which present antigen material to T lymphocytes activating an antigen-specific T-lymphocyte immune response.…”

“…Significant success in the treatment of tumors by DC-EVs has been achieved in murine models and in human cell lines. Other strategies using tumor-derived EVs to deliver antigens to DCs and stimulating GvL are under investigation (110).…”

“…Even though anti-tumor activity of NK-and DC-EVs has been demonstrated in vitro and in preclinical studies (105,110), studies to stimulate GvL after allo-HCT are lacking.…”

Engineered Extracellular Vesicles as a Reliable Tool in Cancer Nanomedicine

“…Regarding EVs' application as cancer therapeutics, it basically differs from conventional approaches, i.e., molecular targeting drugs and chemotherapy. Referring to native EVs, a huge number of in vivo and in vitro studies have been reported [28][29][30][31][32][33][34]. In details, three main approaches in cancer treatment through native EVs can be identified: the inhibition of EVs production [35][36][37], the eradication of circulating EVs, and finally the reduction of EV uptake [38,39].…”