Immunotherapy Using Oxygenated Water and Tumor‐Derived Exosomes Potentiates Antitumor Immune Response and Attenuates Malignancy Tendency in Mice Model of Breast Cancer

Abstract

Breast cancer is one of the most common type of tumor and the leading cause of death in the world’s female population. Various therapeutic approaches have been used to treat tumors but have not led to complete recovery and have even damaged normal cells in the body. Moreover, metastatic tumors such as breast cancer are much more resistant to treatment, and current treatments have not been very successful in treating them and remain a challenge. Therefore, new approaches should be applied to overcome this problem. Given the importance of hypoxia in tumor survival, we aimed to test the antitumor effects of oxygenated water to decrease hypoxia along with tumor-derived exosomes to target tumor. The purpose of administering oxygenated water and tumor exosomes was to reduce hypoxia and establish an effective immune response against tumor antigens, respectively. For this purpose, the breast cancer mice model was induced using the 4T1 cell line in Balb/c mice and treated with oxygenated water via an intratumoral (IT) and/or intraperitoneal (IP) route and/or exosome (TEX). Oxygenation via the IT+IP route was more efficient than oxygenation via the IT or IP route. The efficiency of oxygenation via the two routes along with TEX led to the best therapeutic outcome. Antitumor immune responses directed by TEX became optimized when systemic (IP) and local (IT) oxygenation was applied compared to administration of TEX alone. Results demonstrated a significant reduction in tumor size and the highest levels of IFN-γ and IL-17 and the lowest levels of IL-4 FoxP3, HIF-1α, VEGF, MMP-2, and MMP-9 in the IT+IP+TEX-treated group. Oxygenated water on the one hand could reduce tumor size, hypoxia, angiogenesis, and metastasis in the tumor microenvironment and on the other hand increases the effective immune response against the tumor systemically. This therapeutic approach is proposed as a new strategy for devising vaccines in a personalized approach.

Emerging role of exosomes in cancer progression and tumor microenvironment remodeling

“…Exosomes containing indoleamine 2,3-dioxygenase (IDO) may induce T-cell dysfunction via triggering the IL-6/TNF-α axis [ 293 ]. Future experiments may focus on targeting exosomes in preventing immune evasion and suppressing inflammation to impair cancer progression [ 294 , 295 ].…”

The role of IL-17 in the pathogenesis and treatment of glioblastoma—an update on the state of the art and future perspectives

“…Colon cancer-derived exosomal miR-223-3p promoted M2 macrophage polarization resulting in increased secretion of pro-oncogenic IL-17 which intensified the proliferation and migration of colon cancer cells [ 112 ]. Breast cancer-derived exosomes through increasing the secretion of proinflammatory cytokines such as IL-17 may enhance the anti-tumor immunity and improve the efficacy of immunotherapy in breast cancer patients [ 113 ].…”

Exosome-Mediated Therapeutic Strategies for Management of Solid and Hematological Malignancies

“…Given the relevance of hypoxia in cancer cells’ survival, a study tested the anticancer actions of oxygenated water to reduce hypoxia and cancer-derived exosomes to affect cancer cells. Balb/c mice of the BC model were treated with oxygenated water administered through an intratumoral (IT) or intraperitoneal (IP) route and/or exosome (TEX) [ 36 ]. Results revealed a substantial decrease in cancer dimension, the most significant concentrations of IFN- γ and IL-17, and the slightest concentrations of HIF-1 alpha, MMP-2, MMp-9, IL-4, FoxP3, and VEGF the IT+IP+TEX-treated group [ 36 ].…”