Immunogenic Stress and Death of Cancer Cells in Natural and Therapy-Induced Immunosurveillance

The stimulation of cancer immunosurveillance requires malignant cells to differ from their normal counterparts at two distinct levels. First, cancer cells need to express tumor-associated antigens including neoantigens resulting from somatic mutations, meaning that they are antigenically distinct from parental cells. Second, in response to cell-intrinsic or external stress signals, malignant cells must exhibit or release danger-associated molecular patterns (DAMPs) that function as adjuvant signals. The combination of antigenicity and adjuvanticity results in immunogenicity. Some widely used chemotherapeutics, as well as radiotherapy, can stimulate immunogenic cell death (ICD) to set off an anticancer immune response accounting for long-term therapeutic responses. Here we discuss DAMPs, such as annexin A1, ATP, calreticulin, HMGB1, and type-1 interferons, which are exposed or released from stressed and dying cancer cells in response to ICD inducers and the signal transduction pathways leading to their activation. ICD-associated DAMPs act on receptors that are mostly expressed by immune cells, allowing for the orchestration of an intratumoral immune response that involves the recruitment of dendritic cell precursors, the cross-presentation of tumor antigens, and the induction of a cognate anticancer immune response mediated by interferon-γ producing CD8+ T cells. Failure to emit DAMPs due to cancer cell-intrinsic defects or failure to perceive DAMPs due to mutations or inactivation of the receptors required for their perception (such as the annexin A1 receptor FPR1, the HMGB1 receptor TLR4, or the type-1 interferon receptor IFNAR) weakens anticancer immunosurveillance and has a negative prognostic impact in cancer patients.