In this ‘peek behind the paper’ series, we take a look behind the scenes of a recent Research Article from Nanomedicine entitled, ‘Characterization and antiproliferative activity of glioma-derived extracellular vesicles‘, where we ask corresponding author, Fabrício Figueiró (Universidade Federal do Rio Grande do Sul, Brazil), about his study into characterizing a method to isolate glioma-derived extracellular vesicles (GEVs) and understanding their role in immune system modulation and glioma progression.
Please can you introduce yourself and explain what stimulated your interest in using immunology and nanomedicine to treat gliomas?
My name is Fabrício Figueiró, I’m a pharmacist with a PhD and postdoctoral degree in Biochemistry. Currently, I am a Professor at the Department of Biochemistry at Universidade Federal do Rio Grande do Sul (Porto Alegre, Brazil). I started my scientific life working on basic glioma research in 2006, as an undergraduate. At that time, I worked with glioma preclinical models testing drug-loaded nanoparticles with some promising results. Then, during my PhD, I developed much interest in immunomodulation as part of my research, especially after an exchange program at the University of Pittsburgh (PA, USA).
The cancer microenvironment is now the focus of our research group, with biochemistry and immunology being the central topics and extracellular vesicles, nanotechnology and purinergic signaling as their ramifications. Precisely, in our latest publication, we worked with exosome-enriched extracellular vesicles seeking to understand their role in immunomodulation and glioma progression.
What are the drawbacks of current treatment options for patients with glioma?
Glioblastoma (GBM) is the most aggressive form of a broad category of tumors that arise from glial cells (or their progenitors). Truly, there is no cure or effective treatment for this deadly type of cancer and the most attainable goal is to increase patients’ life expectancy and quality of life. For several decades, the standard of care for GBM patients has slowly evolved and currently, GBM treatment includes surgical resection followed by cytotoxic chemotherapy and radiotherapy. Each of these strategies has its advantages and disadvantages, depending on potential adverse behaviors inherent to the biology of GBM cells and patients’ particularities.
GBM cells are extremely heterogeneous, proliferative and invasive, thus even with a great resection the tumor can recur locally and spread throughout the neighboring tissue. Due to the heterogeneity of this tumor, there is high variability in how the cells will respond to radio/chemotherapy, limiting their effectiveness to GBM cell subpopulations. One of these subsets is especially significant: cancer stem cells. These cells are difficult to target and usually lead to a more aggressive form of tumor after radio/chemotherapy.
Regarding chemotherapy, another drawback is related to the blood–brain barrier – a major limitation is the reduction of anti-cancer drug efficacy, due to low drug penetration. Furthermore, chemotherapy and radiotherapy side effects include normal tissue cytotoxicity and radiation-induced neuronal damage. Other recent and promising forms of cancer treatment have limited efficacy in GBM. No immunotherapy drug, for example, has yet been approved by the US FDA due to a modest effect observed in Phase III clinical trials.
Could you provide us with an overview of the main findings of your research?
In our study, we described a method to isolate GEVs by differential centrifugation from a C6 cell line supernatant. After an initial characterization, our first hypothesis was that GEVs would increase tumor growth given that CD73 expression on GEVs, and consequently, adenosine production, could result in a stronger immunosuppressive environment. Interestingly, our data showed the opposite. Possibly, the adenosine effect is weaker than the GEVs’ immunogenic response. GEVs can decrease glioma progression by modulating the tumor microenvironment, causing a reduction in tumor size by acting on cell proliferation. In addition, GEVs decreased the frequency of T regulatory lymphocytes in the coinjection model and the presence of a regulatory marker (FoxP3) in the coinjection and intranasal models.
With regards to the GEVs that are utilized in your work, which properties allow them to modulate the microenvironment and immune cell activity of glioblastoma?
Tumor EVs play an important role in intercellular communication, interacting with the host’s immune system to modulate the tumor microenvironment. EVs have been brought to the spotlight because of their immunosuppressive or immunostimulatory properties, depending on cellular origin, staging and cell differentiation. In experimental models, protocol settings of EVs-cells/animals exposing, among other factors, also have to be taken into account. Our results have shown that GEVs impact immune cells, but the nature of these interactions and the molecular drivers responsible for them remain poorly understood and require further investigation. Nonetheless, their capacity to modulate cells shifting to an antitumoral immune response is possibly related to:
- EVs express suppressive and stimulatory molecules of their parent cells, particularly tumor-associated antigens, tumor-specific genomic/proteomic signatures, inducing a tumor antigen-specific cytotoxic T-cell response;
- Tumor-derived EVs efficiently deliver unknown tumor antigens to antigen-presenting cells (such as dendritic cells) or CD4+ T cells for cytotoxic T lymphocyte cross-priming;
- EVs can transfer signals that may promote activation of the acceptor cells into immunogenic antigen-presenting cells;
- Another hypothesis that isn’t explored in our study, but is quite plausible, is the ability of EVs to transfer RNAs (miRNAs) to neighboring cells. These miRNAs would be capable of modulating target cells. In the context of our work, these miRNAs might regulate gene expression in immune cells from the tumor microenvironment, controlling many cellular functions such as proliferation, differentiation and weakening the activity of regulatory T cells.
What are the next steps for research into GEVs for the treatment of gliomas?
Cancer vaccines are a promising area for EV therapy, once EVs contain tumor-associated antigens. Cancer (e.g., GBM) vaccine therapy can boost an effective immune response in an ongoing disease rather than the commonly known preventive vaccination concept. Tumor-derived EVs, in this case GEVs, can be engineered to improve their immunogenicity. In addition, some characteristics constitute EVs as an interesting drug-delivery system such as biocompatibility, low toxicity and high specificity for cancer cells in terms of the uptake machinery. From now on we are seeking to understand the immunogenic mechanisms with patient samples on a project that has just recently started.
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Neuro Central or Future Science Group.
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