Inhibitory DAMPs in immunogenic cell death and its clinical implications
Authors:Kazukuni Hayashi1,2, Fotis Nikolos3 and Keith S. Chan1,3
1 Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
2 Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
3 Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
Keywords:
gemcitabine, chemotherapy, damage-associate molecular pattern, immune-checkpoint blockade therapy, immunogenic cell death, prostaglandin E2.
Corresponding Author(s):
Conflict of interest statement:
The authors have no conflict of interest to report.
Please cite this article as:
Kazukuni Hayashi, Fotis Nikolos and Keith S. Chan (2021). Inhibitory DAMPs in immunogenic cell death and its clinical implications. Cell Stress 5(4): 52-54. doi: 10.15698/cst2021.04.247
© 2021 Hayashi et al. This is an open-access article released under the terms of the Crea-tive Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
Abstract:
Dying (or dead) cells are increasingly recognized to impose significant biological influence within their tissues of residence—exerting paracrine effects through proteins and metabolites that are expressed or secreted during cellular demise. For example, certain molecules function as potent mitogens, promoting the repopulation of neighboring epithelial cells. And other myriad of factors—classified as damage-associated molecular patterns (DAMPs)—function as “find me” (attractant), “eat me” (engulfment), or “danger” (activation) signals for recruiting and activating effector immune cells (e.g., dendritic cells) to initiate inflammation. Since the discovery of immunogenic cell death (ICD), the current dogma posits DAMPs as immunological adjuvants for innate immune cell mobilization and activation, which ultimately leads to the antitumoral cross-priming of CD8+ T cells. However, what is currently unknown is how these immunostimulatory DAMPs are counteracted to avoid immune-overactivation. Our recent work builds on these fundamentals and introduces prostaglandin E2 (PGE2) as an ‘inhibitory’ DAMP—a new variable to the ICD equation. Prostaglandin E2 functions as an immunosuppressive counterpoise of adjuvant DAMPs; and thus, mechanistically precludes ICD. Furthermore, the long-debated immunogenicity of gemcitabine chemotherapy was revealed to be contingent on inhibitory DAMP blockade and not due to its inability to promote DAMP expression (i.e., calreticulin) as previously reported. These findings were intriguing. First, despite the presence of gemcitabine-induced hallmark DAMPs, the inhibitory DAMP (i.e., PGE2) was sufficient to hinder the ICD-induced antitumoral immune response (Fig. 1a). And second, rather than pharmacologically substantiating immunostimulatory DAMPs as conventionally approached, the mitigation of the inhibitory DAMP—tipping the immunostimulatory and inhibitory DAMP balance in favor of immunostimulatory DAMPs—was sufficient to render the cell death immunogenic and converted gemcitabine into an ICD-inducing therapy (Fig. 1b). In this microreview, we extrapolate our findings and implicate the value of inhibitory DAMP(s) in drug discovery, its use for clinical prognosis, and as target(s) for therapeutic intervention.