Immunogenic cell death in cancer: concept and therapeutic implications

Abstract

Mammalian cells responding to specific perturbations of homeostasis can undergo a regulated variant of cell death that elicits adaptive immune responses. As immunogenic cell death (ICD) can only occur in a precise cellular and organismal context, it should be conceptually differentiated from instances of immunostimulation or inflammatory responses that do not mechanistically depend on cellular demise. Here, we critically discuss key conceptual and mechanistic aspects of ICD and its implications for cancer (immuno)therapy.

Keywords: Antigenicity; CAR T cells; DAMPs; Immune checkpoint inhibitors; Pattern recognition receptors; Tumor microenvironment.

Fig. 1

Core requirements for the initiation of adaptive immune responses by dying cells. For cell death to drive bona fide adaptive immune responses: (1) cell death must occur in the context of adaptive stress responses; (2) cell death must ultimately occur, as opposed to successful adaptation to stress; (3) dying cells must present antigens that are not covered by thymic tolerance; (4) regulated cell death (RCD) must be accompanied by the emission of endogenous molecules that operate as immunological adjuvants; and (5) microenvironmental conditions must be permissive for antigen-presenting cell (APC) recruitment, maturation and migration to lymph nodes (or other sites of antigen presentation), as well as for cytotoxic T lymphocyte (CTL) infiltration and activation. Depending on which of these conditions is lacking, cell death can drive innate immune signaling coupled with local inflammation, actively promote immunological tolerance and/or result in antigen-specific CTL priming and expansion but no effector immune response. ACD, accidental cell death; DAMP, damage-associated molecular pattern; ICD, immunogenic cell death