Abstract
Cancer immunotherapies have been approved as standard second-line or in some cases even as first-line treatment for a wide range of cancers. However, immunotherapy has not shown clinically relevant success in glioblastoma (GBM). This is principally due to the brain’s “immune-privileged” status and the peculiar tumor microenvironment (TME) of GBM characterized by a lack of tumor-infiltrating lymphocytes and the establishment of immunosuppressive mechanisms. Herein, we explore a local mild thermal treatment, generated via cubic-shaped iron oxide magnetic nanoparticles (size ~17 nm) when exposed to an external alternating magnetic field (AMF), to induce immunogenic cell death (ICD) in U87 glioblastoma cells. In accordance with what has been observed with other tumor types, we found that mild magnetic hyperthermia (MHT) modulates the immunological profile of U87 glioblastoma cells by inducing stress-associated signals leading to enhanced phagocytosis and killing of U87 cells by macrophages. At the same time, we demonstrated that mild magnetic hyperthermia on U87 cells has a modulatory effect on the expression of inhibitory and activating NK cell ligands. Interestingly, this alteration in the expression of NK ligands in U87 cells upon MHT treatment increased their susceptibility to NK cell killing and enhanced NK cell functionality. The overall findings demonstrate that mild MHT stimulates ICD and sensitizes GBM cells to NK-mediated killing by inducing the upregulation of specific stress ligands, providing a novel immunotherapeutic approach for GBM treatment, with potential to synergize with existing NK cell-based therapies thus improving their therapeutic outcomes.
Highlights
Glioblastoma (GBM) is the most common type of primary malignant brain tumor and is one of the most aggressive and lethal forms of cancer, with a median survival rate of 12–15 months following diagnosis [1]
We found that mild magnetic hyperthermia (MHT) modestly downregulated programmed death-ligand 1 (PD-L1) expression on the surface of GBM cells at 24 h after treatment, whereas the exposition to alternating magnetic field (AMF) or iron oxide nanocubes (IONCs) did not produce any significant changes in the surface levels of PD-L1 (Figure S5b in the Supplementary Materials)
Our results demonstrate that mild MHT treatment can be exploited as the external activation mechanism to induce immunogenic cell death (ICD) and re-modulate the immunogenic profile of U87 GBM cells, rendering them more susceptible to the antitumoral action of innate immune effectors, such as macrophages and natural killer (NK) cells
Summary
Glioblastoma (GBM) is the most common type of primary malignant brain tumor and is one of the most aggressive and lethal forms of cancer, with a median survival rate of 12–15 months following diagnosis [1]. The current standard treatment protocol, involving maximal surgical resection of the tumor, followed by concomitant administration of radiotherapy and chemotherapy, the latter mostly with temozolomide (TMZ), has not produced a satisfactory life-extension, and less than 5% of patients diagnosed with. GBM survive for more than 5 years [2]. Pharmaceutics 2021, 13, 1668 lymphomas and solid tumors, the outcomes in GBM patients have been rather disappointing [10].
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