Development of immunogenic cell death inducing materials for cancer immunotherapy

Abstract

Immunogenic cell death (ICD) is distinguished by the release of tumor-associated antigens (TAAs) and danger-associated molecular patterns (DAMPs). This cell death has been studied in the field of cancer immunotherapy due to the ability of ICD to induce antitumor immunity. In this thesis, we develop polypeptide and nanomedicine based ICD inducers for enhanced cancer immunotherapy. In chapter 1, endoplasmic reticulum (ER) stress-mediated ICD inducing fluorinated mitochondria-disrupting helical polypeptides (MDHPs) are reported. The fluorination of the polypeptide provides a high helical structure and potent anticancer ability. This helical polypeptide destabilizes the mitochondrial outer membrane, leading to the overproduction of intracellular reactive oxygen species (ROS) and apoptosis. In addition, this oxidative stress triggers ER stress-mediated ICD. The in vivo results show that co-treatment of fluorinated MDHP and anti-Programmed death-ligand 1 antibodies (αPD-L1) significantly regresses tumor growth and prevents metastasis to the lungs by activating the cytotoxic T cell response and alleviating the immunosuppressive tumor microenvironment. These results indicate that fluorinated MDHP synergizes with the immune checkpoint blockade therapy to eliminate established tumors and to elicit antitumor immune responses. In chapter 2, we develop a tannic acid (TA)-Fe3+ coated doxorubicin (DOX) encapsulated DSPE-PEG micelles (TFDD) as an apoptosis/ferroptosis-mediated ICD inducer for enhanced cancer immunotherapy. By coating TA-Fe3+ on the surface of DOX loaded micelles, an apoptotic agent and a ferroptotic agent are simultaneously delivered into the cancer cells and occur cell death. Furthermore, the oxidative environment in cancer cells generated by apoptosis/ferroptosis hybrid pathway stimulates ER and leads to ICD induction. These results suggest that TFDD results in reinforced ICD induction by apoptosis/ferroptosis-mediated oxidative stress.