Antitumor immune responses mediated by dendritic cells: How signals derived from dying cancer cells drive antigen cross-presentation

Abstract

Dendritic cells (DCs) are essential for the induction of adaptive immune responses against malignant cells by virtue of their capacity to effectively cross-present exogenous antigens to T lymphocytes. Dying cancer cells are indeed a rich source of antigens that may be harnessed for the development of DC-based vaccines. In particular, malignant cells succumbing to apoptosis, rather than necrosis, appear to release antigens in a manner that allows for the elicitation of adaptive immune responses. In this review, we describe the processes that mediate the cross-presentation of antigens released by apoptotic cancer cells to CD8⁺ T lymphocytes, resulting in the activation of protective tumor-specific immune responses.

Keywords: DAMPs; apoptotic; cross-presentation; dendritic cells; necrotic; storage compartments; type 1 interferon.

Figure 1. Experimental induction of cell death. Necrosis can be induced by multiple freeze-thaw cycles using liquid nitrogen. In this setting, both the plasma and nuclear membranes are ruptured so that cellular contents leak out and only membrane debris are left. Apoptosis can be induced by radiation with UV light or γ rays. The membrane of apoptotic cells undergo specific alterations, but (at least initially) it remains intact. Eventually, apoptotic cells also lose membrane integrity, a setting that is often referred to as late apoptosis or secondary necrosis.

Figure 2. CLEC9A direct apoptotic material toward storage compartments. Apoptotic cells are taken up by dendritic cells (DCs). Upon engagement of C-type lectin domain family 9, member A (CLEC9A) on the DC surface, apoptotic cells are directed to RAB5A⁺RAB27A⁺ endosomes. RAB27A rapidly recruits NOX2 to the endosomal membrane, hence preventing an excessive acidification of the maturing endosome and allow for the establishment of a storage compartment. In the absence of CLEC9A the endosomal cargo is quickly dispatcher to lysosomes and fully degraded. CLEC9A thus facilitates the slow degradation and prolonged storage of apoptotic material, a mechanism that may account for the ability of CLEC9A to enhance the cross-presentation of cell-associated antigens.

Figure 3. Type I interferon signaling influences antigen persistence within dendritic cells. Plasmacytoid DCs (pDC) and perhaps also conventional DCs (cDC) produce interferon α (IFNα) upon the recognition of apoptotic cells. The exposure of cDCs to IFNα results in the upregulation of pro-survival factors such as BCL-2 and BCL-X_L; the prolonged storage of apoptotic material in intracellular compartments; and the localization of MHC class I molecules to storage compartments.