Supplementation with Serum-Derived Extracellular Vesicles Reinforces Antitumor Immunity Induced by Cryo-Thermal Therapy

Abstract

Effective cancer therapies should reshape immunosuppression and trigger antitumor immunity. Previously, we developed a novel cryo-thermal therapy through applying local rapid cooling followed by rapid heating of tumor tissue. It could not only ablate local tumors, but also, subsequently, induce systemic long-term antitumor immunity. Hyperthermia can induce the release of extracellular vesicles (EVs) to stimulate antitumor immunity. We examine whether EVs are released after cryo-thermal therapy and whether they could improve the efficacy of cryo-thermal therapy in the 4T1 model. In this study, serum extracellular vesicles (sEVs) are isolated and characterized 3 h after cryo-thermal therapy of subcutaneous tumors. sEV phagocytosis is observed in vitro and in vivo by using laser confocal microscopy and flow cytometry. After cryo-thermal therapy, sEVs are administered to mice via the tail vein, and changes in immune cells are investigated by using flow cytometry. After cryo-thermal therapy, a large number of sEVs are released to the periphery carrying danger signals and tumor antigens, and these sEVs could be phagocytosed by peripheral blood monocytes and differentiated macrophages. After cryo-thermal therapy, supplementation with sEVs released after treatment promotes the differentiation of myeloid-derived suppressor cells (MDSCs), monocytes into macrophages and CD4+ T cells into the Th1 subtype, as well as prolonging the long-term survival of the 4T1 subcutaneous tumor-bearing mice. sEVs released after cryo-thermal tumor treatment could clinically serve as an adjuvant in subsequent cryo-thermal therapy to improve the therapeutic effects on malignant tumors.

Physical modulation of mesenchymal stem cell exosomes: A new perspective for regenerative medicine

“…Accumulated studies have reported that heat stress exerted significant effects on both the volume and contents of exosomes produced by various sources, including cancer cells, immune cells and blood 184–186 . Cryo‐thermal therapy can induce the release of serum‐derived exosomes and enhance their immunoregulation ability 187 . However, further studies are required to determine whether alterations occur in the secretion and biological functions of MSC‐Exo under varying temperature.…”

“… 184 , 185 , 186 Cryo‐thermal therapy can induce the release of serum‐derived exosomes and enhance their immunoregulation ability. 187 However, further studies are required to determine whether alterations occur in the secretion and biological functions of MSC‐Exo under varying temperature. Additionally, exploring whether pre‐treatment at different temperatures can be considered a strategy to enhance the resilience of MSC‐Exo in extreme environments is a promising avenue for future research.…”

Extracellular‐Vesicle‐Based Drug Delivery Systems for Enhanced Antitumor Therapies through Modulating the Cancer‐Immunity Cycle

“…[106] Therefore, the isolation method of EVs should be chosen appropriately based on specific applications, advantages, and limitations listed in Table 1. [92] To obtained EVs with high yield, starvation, [107,108] UV irradiation, [57,58,109] heating, [110] etc., were used to stimulate parent cells to secrete more EVs.…”