Fig. 3

Immunogenic Cell Death (ICD) and Tolerogenic Cell Death (TCD). Immunogenic cell death can be induced by a variety of mechanisms that are still being defined, including low dose radiation, low dose chemotherapy, oncolytic viruses and others. ICD triggers translocation or release of DAMP factors from the dying cell in distinct spatiotemporal patterns that shape the subsequent immune response. DAMPs engage with receptors on antigen presenting cells (APCs) and, in combination with tumor-associated antigens and type I IFN, trigger APC activation, maturation, and trafficking to draining lymph nodes. This process can be augmented with TLR agonists in some instances. Once in the lymph node, APCs engage with cognate T cells and drive T cell activation and proliferation. T cells then traffic to the tumor via CXCL9/10/11 gradients induced by type I IFN signaling in tumor cells, which can result in rapid tumor elimination and generation of long term protective immune memory. In contrast, TCD including most forms of apoptosis is a non-inflammatory pathway for cell death which is characterized by membrane blebbing and loss of DAMP secretion, with sequestration of high-mobility group protein 1 (HMGB1) and phosphatidylserine exposure on the cell surface. Consequently, pro-inflammatory cytokines including IL-1 and TNF are not released to activate endothelium and recruit other T cells. Ectonucleotidases CD39 and CD73 degrade ICD-associated ATP to adenosine thereby inhibiting T and NK cell responses with expression of the A2A adenosine receptor (ADORA2A). This mechanism is used by regulatory T cells (Treg) and inhibits T cell effector function. An immunosuppressive environment characterized by enhanced myeloid derived suppressor cells and regulatory T cells is established while T cells fail to activate and form a productive immune response