Immuno-Surgical Management of Pancreatic Cancer with Analysis of Cancer Exosomes

Abstract

Exosomes (EXs), a type of extracellular vesicles secreted from various cells and especially cancer cells, mesenchymal cells, macrophages and other cells in the tumor microenvironment (TME), are involved in biologically malignant behaviors of cancers. Recent studies have revealed that EXs contain microRNAs on their inside and express proteins and glycolipids on their outsides, every component of which plays a role in the transmission of genetic and/or epigenetic information in cell-to-cell communications. It is also known that miRNAs are involved in the signal transduction. Thus, EXs may be useful for monitoring the TME of tumor tissues and the invasion and metastasis, processes that are associated with patient survival. Because several solid tumors secrete immune checkpoint proteins, including programmed cell death-ligand 1, the EX-mediated mechanisms are suggested to be potent targets for monitoring patients. Therefore, a companion therapeutic approach against cancer metastasis to distant organs is proposed when surgical removal of the primary tumor is performed. However, EXs and immune checkpoint mechanisms in pancreatic cancer are not fully understood, we provide an update on the recent advances in this field and evidence that EXs will be useful for maximizing patient benefit in precision medicine.

Keywords: cancer; exosome; immunology; surgery.

Figure 1

Exosomes can transfer information via cell-to-cell communications. Exosomes (EXs) are membrane vesicles secreted from many kinds of cells. EXs contain various secretory cell-derived proteins and RNA, including endosome-derived proteins, proteins involved in intracellular transport and cell membrane-derived proteins. In addition, they contain lipids derived from the cell membrane of endocrine cells and endosomal membranes. EXs taken up by the target cells fuse with their endosomal membrane to release the contained RNAs into the cytoplasm of the target cells. A released mRNA is translated into a protein, whereas the miRNAs suppress the translation of the target gene and thus EXs control the gene expression in the target cell. In addition, these EXs components are different from those in EX secretory cells. Therefore, a specific mechanism by which EX proteins and mRNA/miRNA are selectively loaded into EXs was suggested.

Figure 2

Exosome-mediated PD1 and PDL1 pathways. Interferon-γ (IFNγ) produced by T cells upregulates PDL1 expression in many tumor cells and stimulates endosomes or the multivesicular body to secrete extracellular vesicles and exosomes. When PD1 expressed on activated T cells binds to PDL1 expressed on cancer cells or antigen-presenting cells, T-cell activation is suppressed, and immune escape of cancer cells occurs in the tumor microenvironment.