Immunogenic cell death inducers as anticancer agents

It has been widely thought that the occasional success of anticancer chemotherapies is mediated by direct, efficient cytostatic or (better) cytotoxic effects of the antineoplastic agent on tumor cells. Nonetheless, there is accumulating evidence for the hypothesis that long-term clinical success (which is measured in years and decades rather than weeks and months) involves anticancer immune responses that are often mediated by T lymphocytes recognizing tumor-specific antigens. During recent years, a whole catalogue of mechanisms through which chemotherapeutics can stimulate immune responses has emerged. Thus, some therapeutic agents can stimulate immune effector cells either directly or – more frequently – by subverting the immunosuppressive circuitries that block antitumor immune responses [1]. In addition, some chemotherapeutic agents provoke immunogenic cancer cell death (ICD), meaning that they induce tumor cell death in a way that those cells elicit a specific immune response. ICD is characterized by a series of alterations that usually do not occur in the context of apoptosis: (i) the pre-apoptotic exposure of calreticulin (CRT) on the cell surface, (ii) release of ATP during the blebbing phase of apoptosis, and (iii) post-apoptotic exodus of the chromatin-binding protein high mobility group B1 (HMGB1). CRT exposure critically depends on a premortem endoplasmic reticulum stress response, ATP release on premortem autophagy, and HMGB1 exodus on secondary necrosis. CRT, ATP and HMGB1 bind to three receptor types (CD91 receptor, purinergic P2Y2 or P2X7 receptors, and toll-like receptor 4, respectively) that are present on dendritic cells or their precursors. CD91, P2Y2, P2RX7 and TLR4 promote engulfment of dying cells, attraction of dendritic cells into the tumor bed, production of interleukin-1β and presentation of tumor antigens, respectively [2]. Since (some of) the molecular characteristics of ICD are well studied, it has been possible to screen compound libraries for the presence of ICD inducers, which would cause (i) CRT exposure, (ii) ATP release and (iii) HMGB1 exodus in cultured human cancer cells [3]. Agents that induce the hallmarks of ICD in vitro could be validated by in vivo experiments using two complementary assays. First, it was possible to test the capacity of candidate ICD inducers to kill mouse cancer cell lines in vitro so that the resulting dead-cell preparation would elicit protective anticancer immune responses upon its subcutaneous injection into immunocompetent, syngenic mice. Second, the anticancer effects of ICD inducers on established tumors were found to be more efficient if such tumors evolved in immunocompetent (as opposed …