Damage-associated molecular patterns in cancer: a double-edged sword

Abstract

Damage-associated molecular patterns (DAMPs) are released in response to cell death and stress, and are potent triggers of sterile inflammation. Recent evidence suggests that DAMPs may also have a key role in the development of cancer, as well as in the host response to cytotoxic anti-tumor therapy. As such, DAMPs may exert protective functions by alerting the immune system to the presence of dying tumor cells, thereby triggering immunogenic tumor cell death. On the other hand, cell death and release of DAMPs may also trigger chronic inflammation and, thereby promote the development or progression of tumors. Here, we will review the contribution of candidate DAMPs and their receptors, and discuss the evidence for DAMPs as tumor-promoting and anti-tumor effectors, as well as unsolved questions such as DAMP release from non-tumor cells as well as the existence of tumor-specific DAMPs.

Fig 1. DAMPs mediate tumor progression

Cellular release of DAMPs such as uric acid, HMGB1, S100 proteins, IL-1α and adenosine can promote tumor progression via distinct mechanisms and target cells. Adenosine and HMGB1 may contribute to immunosuppression, HMGB1 and IL-1α to angiogenesis; uric acid, HMGB1, S100 proteins and adenosine to tumor cell proliferation; and ATP, IL-1α, S100 proteins, HMGB1 and uric acid to inflammation. NK, natural killer cell; MDSC, myeloid-derived suppressor cell; DC, dendritic cell; EC, endothelial cell.

Fig 2. Contribution of DAMPs to tumor rejection via ICD

Immunogenic cell death (ICD), induced by various anti-cancer therapies strongly relies on the activation of DAMP signaling pathways. Following exposure irradiation, treatment with select chemotherapeutic agents and or infections with oncolytic viruses, tumor cells release DAMPs in the following order: 1. pre-apoptotic exposure of the ER chaperone calreticulin on the cell surface (ecto-CRT); 2. early apoptotic secretion of ATP; 3. post-apoptotic release of HMGB1. These DAMPs engage their respective receptors including CD91, P2X7R, P2Y2R, RAGE and TLR4 on the surface of dendritic cells (DC), triggering DC engulfment of dying cells, tumor antigen processing and presentation. In addition, Annexin A1, via its receptor FPR1, is required to bring DC into close proximity to dying tumor cells. DC maturation and activation ultimately foster potent anti-tumor responses via recruitment and activation of CD4+ and CD8+ T cells and natural killer (NK) cells.