Graphene-Induced Hyperthermia (GIHT) Combined With Radiotherapy Fosters Immunogenic Cell Death

Abstract

Radiotherapy and chemotherapy are the standard interventions for cancer patients, although cancer cells often develop radio- and/or chemoresistance. Hyperthermia reduces tumor resistance and induces immune responses resulting in a better prognosis. We have previously described a method to induce tumor cell death by local hyperthermia employing pegylated reduced graphene oxide nanosheets and near infrared light (graphene-induced hyperthermia, GIHT). The spatiotemporal exposure/release of heat shock proteins (HSP), high group mobility box 1 protein (HMGB1), and adenosine triphosphate (ATP) are reported key inducers of immunogenic cell death (ICD). We hypothesize that GIHT decisively contributes to induce ICD in irradiated melanoma B16F10 cells, especially in combination with radiotherapy. Therefore, we investigated the immunogenicity of GIHT alone or in combination with radiotherapy in melanoma B16F10 cells. Tumor cell death in vitro revealed features of apoptosis that is progressing fast into secondary necrosis. Both HSP70 and HMGB1/DNA complexes were detected 18 hours post GIHT treatment, whereas the simultaneous release of ATP and HMGB1/DNA was observed only 24 hours post combined treatment. We further confirmed the adjuvant potential of these released DAMPs by immunization/challenge experiments. The inoculation of supernatants of cells exposed to sole GIHT resulted in tumor growth at the site of inoculation. The immunization with cells exposed to sole radiotherapy rather fostered the growth of secondary tumors in vivo. Contrarily, a discreet reduction of secondary tumor volumes was observed in mice immunized with a single dose of cells and supernatants treated with the combination of GIHT and irradiation. We propose the simultaneous release of several DAMPs as a potential mechanism fostering anti-tumor immunity against previously irradiated cancer cells.

Anticancer and Anti-Inflammatory Mechanisms of NOSH-Aspirin and Its Biological Effects

“…The pro-apoptotic activity of NOSH-Aspirin is undoubtedly a new route for the research of antitumor drugs. Literature has shown that while promoting apoptosis, it will also increase the sensitivity of tumor cells to radiotherapy and chemotherapy [ 60 ]. This also suggests a new direction for whether NOSH-Aspirin could be used as a radiation and chemotherapy adjuvant.…”

The Effect of Hyperthermia and Radiotherapy Sequence on Cancer Cell Death and the Immune Phenotype of Breast Cancer Cells

“…Immunogenic cancer cell death (ICD) is one of the key triggers that has been reported by several studies to induce anti-tumor immune responses [52]. Indeed, ICD can be induced by a combination of RT with, e.g., graphene-induced HT [53], but also with conventional heat application, as shown, e.g., for colorectal cancer cells [17]. ICD mainly triggers the activation of DCs via the release of danger signals and consecutive cytotoxic T cell priming [54].…”

Role of HMGB1 in Cutaneous Melanoma: State of the Art

“…Indeed, HSP70, HMGB1/DNA complexes and ATP, markers of ICD, were detected. Chronic inflammation is linked to tumorigenesis and extracellular HMGB1 behaves like a pro-inflammatory cytokine that induces the expression of further inflammatory factors, favoring the persistence of the inflammation mechanism which in turn manipulates the immune system [ 60 ].…”