Immunomodulation in wound healing and oncogenesis
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Abstract
Immunotherapy has emerged as a promising approach to treat a wide range of clinical conditions. Herein, immunomodulatory agents are applied to induce favorable immune responses. Depending on the condition, immune responses may be amplified (e.g., cancer) or attenuated (e.g., wound healing). Cancer and deficiencies in wound healing represent significant global healthcare burdens. Cancer is the second leading cause of death worldwide, and more than 40 million people are suffering from chronic wounds. Although the incidence of both conditions is increasing, many patients still lack effective treatment options. Therefore, the development of novel immunomodulatory approaches to treat these conditions is an upmost priority.
Before these approaches can be developed into therapies, they must first be thoroughly characterized to ensure their safety and efficacy. Therefore, this cumulative dissertation characterized two novel immunomodulatory approaches, namely the protein, glycoprotein A repetitions predominant (GARP) as a new target, and cold atmospheric plasma (CAP) as a device, in the immunological contexts of cancer and wound healing.
In the past, GARP was described as a potent mechanism of immune tolerance through its regulation of the suppressive cytokine, transforming growth factor beta (TGF-β). The present work provides some of the first insights into the role of GARP in wound healing and in cancer stem cell biology. In “GARP Regulates the Immune Capacity of a Human Autologous Platelet Concentrate”, the immunological influence of GARP in injectable platelet rich fibrin (iPRF) was investigated. It was determined that GARP mediates T cell immunity by inducing regulatory T cells, a key cell type that facilitates the wound healing process. Conversely, GARP was found to inhibit the production of proinflammatory cytokines, which can prevent effective wound healing by sustaining chronic inflammation. Application of an anti-GARP antibody reversed these effects.
The present work analyzed another aspect of GARP biology, namely its role in glioblastoma stem-like cells (GSCs). GSCs are a small subset of tumor cells, which drive tumor initiation, therapy resistance, and recurrence in glioblastoma. Prior to this study, no markers had been found that were universally expressed by all GSCs due to their innately high heterogeneity. In “Nuclear Glycoprotein A Repetitions Predominant (GARP) Is a Common Trait of Glioblastoma Stem-like Cells and Correlates with Poor Survival in Glioblastoma Patients”, GARP was evaluated and confirmed as a possible marker for GSCs. Functionally, GARP was found to be implicated in the self-renewal of GSCs. Due to the high expression of GARP on GSCs, the protein was also investigated as a prognostic biomarker for glioblastoma. Hereby, the abnormal nuclear localization of the protein was linked to reduced overall survival of patients with glioblastoma for the first time.
The immunomodulatory effects of CAP were examined in the context of cancer. CAP is a partially ionized gas, which is also compromised of neutral atoms, excited electrons, and electromagnetic radiation. In contrast to thermal plasma, CAP can be applied within physiological temperatures. CAP has been reported to selectively target cancer cells by increasing exogenous reactive oxygen and nitrogen species (RONS). Prior to this work, little was known regarding how CAP influences immune cells, key determiners of immunotherapy response in the melanoma microenvironment. In “Oxidative Stress Differentially Influences the Survival and Metabolism of Cells in the Melanoma Microenvironment”, the effects of CAP on T cells, macrophages, and tumor cells were investigated. All cell types exhibited signs of oxidative stress following CAP treatment, but T cells were the most sensitive. These effects could be partially reversed with the application of antioxidants. Surprisingly, CAP was found to influence the polarization of macrophages to an anti-inflammatory “M0/M2” phenotype.
Collectively, this work sheds light on the immunomodulatory properties and functional relevance of GARP and CAP in distinct immunological settings. In the future, these immunomodulatory mechanisms might be used as possible therapeutic approaches to elicit favorable immune responses in the treatment of cancer and the optimization of wound healing.