Development of a thiazole-containing alpha helical artificial polypeptide as immunogenic cell death inducer for effective cancer immunotherapy

Abstract

Immunogenic cell death (ICD) has emerged as a promising approach to cancer immunotherapy. The ICD provokes cancer cell death and simultaneously makes cancer cells release damage-associated molecular pattern (DAMP) signals. To induce enhanced level of ICD, endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation of damaged cancer cells are pivotal. Excessive released ROS react with glutathione (GSH) and are involved in various cell death mechanisms. Recently thiazole core of many drugs gained considerable interest because of its antiproliferative activity such as DNA fragmentation, mitochondrial dysfunction, cell cycle arrest, and inhibition of proteasome activity. We developed and synthesized positive charged cell penetrating polypeptide which of side chains are modified with thiazole, a five membered sulphur and nitrogen containing ring, structure (NSP). It can easily penetrate cellular membrane not only because of its alpha helical structure itself, but also through endo-lysosomal escape. It can simultaneously provoke significant ROS production and ER stress, resulting in enhanced DAMP signals. Depending on the concentration, the GSH activity decreased and the degree of DNA fragmentation was significantly changed, which led cell death pathway to be switched from apoptosis to necroptosis at higher concentration. In this study, we confirmed the possibility of NSP as a promising ICD inducer that can be used while varying the concentration according to the environment for cancer immunotherapy.