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.
Highlights
Every anti-tumor therapy aims to induce immunogenic cell death (ICD), which favors the development of specific antitumor responses
Graphene-Induced Hyperthermia (GIHT) Triggers Apoptosis Rapidly Followed by Secondary Necrosis
The survival of cancer patients has been negatively correlated with tolerogenic apoptosis [39], and primary necrosis was shown to lack of immunogenicity [4]
Summary
Every anti-tumor therapy aims to induce immunogenic cell death (ICD), which favors the development of specific antitumor responses. The spatiotemporal exposure of calreticulin on the outer leaflet of the plasma membrane [1, 2], the secretion of ATP [3, 4], and the release of DAMPs such as HMGB1 [4–6], heat shock protein 70 (HSP70) [7, 8] and HSP90 [4, 9] are essential organic adjuvants required to induce ICD. These signals are recognized by various pattern recognition receptors on antigen presenting cells facilitating their activation and migration to draining lymph nodes followed by induction of potent adaptive immune response [10]. Some mediators released by dying cells, such as Prostaglandin E2 or adenosine, show immunosuppressive features contributing to the tolerance [11, 12] and growth of tumor cells [13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
