Immunogenic cell death in the murine B16F10-Nex2 melanoma model: a new immunotherapeutic alternative?

Abstract

Melanoma, the type of skin cancer showing the highest mortality rate, is classically treated with chemo and radiotherapy protocols, but the prognosis of the disease improves significantly only with early diagnosis. The efficacy of the currently available treatments is still very low for metastatic melanoma. Immunotherapeutic protocols have shown promising results. Good results with Ipilimumab and Nivolumab, monoclonal antibodies that block respectively the activation of CTL-4 and PD-1, negative modulators of cytotoxic T lymphocytes, demonstrate that the activation of immune system in melanoma's patients is very promising. Recently it has been shown that some chemotherapeutic drugs with high antitumor activity (oxaliplatin and a few others) are able to modulate the immune system in addition to their direct action against tumor cells. These drugs induce the translocation and secretion of DAMPS (damage associated molecular patterns) by dying tumor cells, and these molecules bind to specific receptors activating the immune system, therefore enhancing specific antitumor immune response. This effect has been called Immunogenic Cell Death. To date just a few available antitumor drugs induce immunogenic cell death, and that makes extremely relevant the discovery of new compounds able to induce tumor cell death and also activation of the immune system. Our group has described a new compound derived from Ruthenium, which showed a high activity against murine B16F10 melanoma and murine 4T1 breast adenocarcinoma. This new compound led to tumor cell death in vitro and control of tumor growth in vivo, in both primary and metastatic models. Thus this project aims to assess whether the high antitumor activity showed by nitrosyl ruthenium tetraamine-sulfated compound (RuImNSO4) can be related to the induction of immunogenic cell death in tumor cells. In vitro experiments will evaluate the presence of immunogenic cell death markers in tumor cells treated with this compound. In vivo experiments will determine the ability of the immunization with RuImNSO4-treated cells to induce antitumor protective immunity, and tumor-specific immune response and also reduction of tumor development in animals immunized with treated cells and subsequently challenged with viable cells will be measure.