Exosomes reveal the dual nature of radiotherapy in tumor immunology

Abstract

Radioresistance is the potential cause of cancer metastasis and recurrence. Radiation-induced changes in exosomes can partially explain the undesirable prognosis of radiotherapy (RT). Exosomes, newly discovered ways of cell communication, carry the characteristics of their origin, resulting in their diversity. Various exosomes in the tumor microenvironment exert different function in immune response. In this review, the dual effect of RT on the immune system was described, and the effect of radiotherapy on tumors via exosomes was explored. The molecules in exosomes after RT were described to play immunosuppressive and immunocompetent roles: immune-related receptors and cell signaling molecules involved in both adaptive and innate immune system were present. CD69, TIGIT, TIM-3, LAG-3 and the tumor necrosis factor (TNF) family that signal to T cells were shown to be regulated by exosomes after irradiation. The change in innate immunity-derived like receptors, Leukocyte Immunoglobin-Like Receptors (LILR) was described, as well as B7-H3, V-domain containing Ig suppressor of T cell activation (VISTA), and CD155 on tumor cells. These changed molecules inhibit and activate the immune system through different mechanisms. By analyzing the relationship between exosome-derived molecules and immunity, this review shows that radiotherapy can induce immunosuppression and immune clearance through exosomes, thereby treating tumors and improving patient prognosis.

Keywords: cancer; exosome; immunomodulation; radiotherapy.

FIGURE 1

Schematic diagram of the structures of exosomes. Exosome membrane contain MHC proteins, tetraspanins, and other transmembrane proteins for cellular communication. Exosomes contain cytosolic proteins such as heat shock proteins, metabolic enzymes, and cytoskeletal proteins

FIGURE 2

Schematic diagram of the immunosuppressive effect of radiotherapy (RT) with associated exosomes. Tumor cells and immune cells in acquired and congenital pathways are capable of releasing or receiving exosomes generated by RT to adjust the immune system into a depressed state. Exosomal MHC Ⅰ, miR‐590‐3p, SIRPα, and miR‐378a‐3p are increased in association with innate immunity. Exosomal PD‐L1, B7‐H3, TIGIT, TIM‐3, and LAG‐3 levels are increased in association with adaptive immunity

FIGURE 3

Schematic diagram showing the immunocompetent aspects of radiotherapy (RT) and exosomes involved. The cell damage caused by RT increases the number of immunogenic molecules that then activate T cells to exert an antitumor response. The cell death caused by radiation activates T cells through exosomal calreticulin (CRT) and CCR7 and increases CD86/CD28/CD47 levels and the expression of receptors 4‐1BB, OX40, and GITR