Apr 27, 2020

The Injury Response to DNA Damage Promotes Anti-Tumor Immunity

BioRxiv : the Preprint Server for Biology
G. SriramMichael B. Yaffe

Abstract

Inhibition of immune checkpoints has shown promising results in the treatment of certain tumor types. However, the majority of cancers do not respond to immune checkpoint inhibition (ICI) treatment, indicating the need to identify additional modalities that enhance the response to immune checkpoint blockade. In this study, we identified a tumor-tailored approach using ex-vivo DNA damaging chemotherapy-treated tumor cells as a live injured cell adjuvant. Using an optimized ex vivo system for dendritic cell-mediated T-cell IFN-{gamma} induction in response to DNA-damaged tumor cells, we identified specific dose-dependent treatments with etoposide and mitoxantrone that markedly enhance IFN-{gamma} production by T-cells. Unexpectedly, the immune-enhancing effects of DNA damage failed to correlate with known markers of immunogenic cell death or with the extent of apoptosis or necroptosis. Furthermore, dead tumor cells alone were not sufficient to promote DC cross-presentation and induce IFN-{gamma} in T-cells. Instead, the enhanced immunogenicity resided in the fraction of injured cells that remained alive, and required signaling through the RIPK1, NF-kB and p38MAPK pathways. Direct in vivo translation of these findings was accompli...Continue Reading

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Mentioned in this Paper

Gene Polymorphism
Patterns
ST2 protein, rat
Contrast Used
Adaptation
Simulation
Species
Genetic Polymorphism
2,2'-(5,5'-(9,9-didecyl-9H-fluorene-2,7-diyl)bis(ethyne-2,1-diyl)bis(thiophene-5,2-diyl))dibenzo(d)thiazole
Alpha Tocopherol

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