Identification and in vitro preclinical study of natural compounds and derivatives as inducers of immunogenic cell death

A number of studies in the past decade consistently indicates that effectiveness of a variety of anti-cancer treatments, initially meant to directly inhibit tumor cell survival and proliferation, is actually based on immune system activation. Defined cytotoxic or genotoxic agents promote the generation of anticancer immune responses, potentially leading to tumor eradication, by inducing in malignant cells immunogenic cell death (ICD). The ability of different synthetic chemotherapeutic drugs to induce ICD has been characterized in detail. In contrast, there is a paucity of data regarding natural products of potential clinical relevance. I provided a comprehensive preclinical, in vitro study of cell death mechanisms and immunologic characteristics of two botanical drugs, Withania somnifera (WS) and Hemidesmus indicus (HI), and one isothiocyanate (ITC) derivative synthesized ad hoc in order to reach the ER, MG28. MG28 didn’t give the expected results and the study was interrupted, while both botanical drugs resulted able to trigger the main in vitro hallmarks of ICD. The most promising agent was HI. I demonstrated its ability to trigger oxidative and endoplasmic reticulum stress, two crucial events for the exploitation of ICD immunogenicity, then I proved its proficiency to positive modulate the expression and mobilization of ICD mediators, the so-called damage associated molecular patterns. Prompted by these observations, I addressed HI’s ability to promote the activation of immature dendritic cells (iDC) and explored its immunomodulatory ability. Data consistently indicate that HI-treated tumor cell supernatants are able to promote the transition from an immature to a mature state of in vitro generated professional antigen-presenting cell (APC). On the whole, the evidence reported in this thesis shows and confirms the remarkable potential of natural products in the oncological area and highlights their ability to induce ICD.