Abstract
BackgroundInterleukin-12 (IL-12) has long been considered to be effective in triggering an anticancer immune response, however, the dosage has been limited by potential systemic immunotoxicity. Since focused ultrasound (FUS) has been confirmed to temporally and locally open the blood–brain barrier (BBB), the purpose of this study was to elucidate the possibility of combining FUS-induced BBB opening with IL-12 delivery to enhance the anticancer immunological response for glioma treatment.MethodsFUS energy combined with microbubble administration was delivered transcranially to open BBB, and C-6 glioma rats were used in this study. The efficacy in inducing BBB opening and the corresponding immunological response were primarily evaluated in normal animals. The anticancer immune-triggering chemokine, IL-12, was intraperitoneally administered during the treatment phase to evaluate the effect of immunological response on tumor progression. Glioma animals were sub-grouped to evaluate the effect of the immune response in suppressing glioma when IL-12 was combined with FUS-induced BBB opening. We performed flow cytometry to verify consequent immune cell population changes of peripheral/tissue lymphocytes as well as macrophages from the animals. Brain sections of sacrificed animals were also used for histological and immunohistochemical analysis. IL-12 level among experimental groups were measured via ELISA analysis. We also analyzed survival and followed tumor progression in vivo via T2-weighted magnetic resonance imaging.ResultsFUS-induced BBB opening had no obvious effect on the T lymphocytes population in normal animals, either in the brain or systemically. Yet, it triggered mild changes in the tumor-infiltrating lymphocyte (TIL) population, particularly in numbers of CD3+CD8+ cytotoxic T lymphocytes (CTLs) in the tumor region. IL-12 administration triggered a profound increase in all TIL populations, including CD3+CD4+ T helper cells (Th), CTL, and CD4+CD25+ regulatory T cells (Treg), but combined FUS-BBB opening with IL-12 administration produced the most significant IL-12 increase, CTL increase and CTL/Treg ratio increase, thus contributing to the most significant suppression of tumor progression and increased animal survival.ConclusionThis study provides evidence that FUS-BBB opening can enhance immune-modulating agent delivery to the brain, which improve the anticancer immune response in brain tumor treatment.
Highlights
260,000 patients worldwide are diagnosed annually with primary malignant brain cancers, among which, more than 50% are reported to have glioblastoma multiforme (GBM) [1]
focused ultrasound (FUS) has minimal effect on T cell components in normal rat brain Figure 2(A) shows typical brain sections stained with Evans blue to mark the blood–brain barrier (BBB)-opened regions in normal rats
When a higher exposure level of 20 W was applied, the BBB-opened regions spread toward a wider area, with RBCs extravasated in the exposure regions
Summary
260,000 patients worldwide are diagnosed annually with primary malignant brain cancers, among which, more than 50% are reported to have glioblastoma multiforme (GBM) [1]. The current approach for brain tumor therapy is surgical resection with radiotherapy, which is typically accompanied by adjuvant and chemotherapy or other therapeutic molecule substance delivery into the tumor site [4,5]. The BBB of the peripheral glioma has been shown to remain highly functional [7,8,9], and previous clinical studies have demonstrated that brain tumor cells can migrate great distances from the enhancing regions of the tumors [10]. Since focused ultrasound (FUS) has been confirmed to temporally and locally open the blood–brain barrier (BBB), the purpose of this study was to elucidate the possibility of combining FUS-induced BBB opening with IL-12 delivery to enhance the anticancer immunological response for glioma treatment
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