Exosomes derived from cancerous and non-cancerous cells regulate the anti-tumor response in the tumor microenvironment

Abstract

The tumor microenvironment (TME) is a unique platform of cancer biology that considers the local cellular environment in which a tumor exists. Increasing evidence points to the TME as crucial for either promoting immune tumor rejection or protecting the tumor. The TME includes surrounding blood vessels, the extracellular matrix (ECM), a variety of immune and regulatory cells, and signaling factors. Exosomes have emerged to be molecular contributors in cancer biology, and to modulate and affect the constituents of the TME. Exosomes are small (40-150 nm) membrane vesicles that are derived from an endocytic nature and are later excreted by cells. Depending on the cells from which they originate, exosomes can play a role in tumor suppression or tumor progression. Tumor-derived exosomes (TDEs) have their own unique phenotypic functions. Evidence points to TDEs as key players involved in tumor growth, tumorigenesis, angiogenesis, dysregulation of immune cells and immune escape, metastasis, and resistance to therapies, as well as in promoting anti-tumor response. General exosomes, TDEs, and their influence on the TME are an area of promising research that may provide potential biomarkers for therapy, potentiation of anti-tumor response, development of exosome-based vaccines, and exosome-derived nanocarriers for drugs.

Keywords: angiogenesis; exosomes; immunoregulation; immunotherapy; tumor-derived exosomes.

Figure 1. Exosome production and detection

Exosomes are small (50–90 nm) membrane vesicles that are endocytic in origin and are released into the extracellular environment upon fusion with the plasma membrane. They are formed by multi-vesicular bodies, which release the exosomes into the surrounding environment. Isolation of exosomes is performed through differential centrifugation, from which the contents are then analyzed through Western Blog, FACS, and MALDI-TOF. Various cell types, including immune cells and cancer cells, release exosomes carrying a multitude of cargo, including but not limited to as microRNAs, mRNAs, and tumor antigens.

Figure 2. Tumor-derived exosome

Tumor-derived exosomes (TDEs) are aid in the recruitment and reprogramming of the TME. They express various oncogenic factors that enhance tumorigenesis.

Figure 3. Exosome-mediated immune regulation

1) Tumor cells release exosomes (TDEs) that consequently affect numerous immune cells. 2) MHC-peptide complexes participate in direct antigen presentation to activate a CD8+ T cell response. 3) TDE antigens combined with MHC Class II molecules released from B cells also serve to activate CD8+ T cells. 4) However, TDEs can also induce apoptosis of activated CD8+ T cells, via TDE-bound FasL and exosomal TRAIL. 5) TDEs also drive the differentiation, via TGF-β and PGE₂, of myeloid precursor cells to MDSCs, which release immunosuppressive factors NO and ROS. 6) Immune-cell derived exosomes, as from a dendritic cell, influence the TME and have been shown to boost NK cell immune response. However, TDEs combat this effect by downregulation of NKG2D receptors on NK cells. 7) DC-derived exosomes also stimulate CD4+ T cell response, which synergistically works with DC-derived exosomal cargo to inhibit Treg cells.