The success of most if not all anticancer treatments depends on the (re)activation of immunosurveillance, as this has been documented for several therapeutic modalities, not only immunotherapy, but also chemotherapy, targeted therapy and radiotherapy. In response to antineoplastic drugs, malignant cells can undergo immunogenic cell death (ICD), thus exposing and releasing danger signals that act on pattern recognition receptors expressed by immune cells, in particular dendritic cells (DCs), to trigger the first steps of a therapeutically relevant anticancer immune response. Based on solid preliminary data and novel methodological approaches, we propose to obtain fundamental insights into the physicochemical properties and molecular mode of action of pharmacological ICD inducers (Task 1), to create chemical-genetic systems for “synthetic” ICD induction for the study of ICD effects on the immune system without perturbation by pleiotropic anticancer drugs (Task 2) and to identify new ICD-relevant immune checkpoints acting at the level of DCs (Task 3). We will use this knowledge to generate an integrated view of the cancer-immune dialogue ignited, on one side, by malignant cells succumbing to ICD and, on the other side, DCs perceiving ICD, hence developing optimal strategies for the stimulation of tumor immunosurveillance (Task 4). The concept of ICD has already been useful for patient-relevant biomarker discovery, drug development and trial design, strongly suggesting that a deeper exploration of this phenomenon will yield clinically relevant information.
