Biological responses to type I interferons: relationship to therapeutic effects in multiple sclerosis

2019 ◽  
pp. 430-445
2018 ◽  
Author(s):  
Jianfeng Shen ◽  
Wei Zhao ◽  
Zhenlin Ju ◽  
Lulu Wang ◽  
Yang Peng ◽  
...  

AbstractPoly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have shown remarkable therapeutic efficacy against BRCA1/2 mutant cancers through a synthetic lethal interaction. PARPis are believed to exert their therapeutic effects mainly through the blockade of single-strand DNA damage repair, which leads to the accumulation of toxic DNA double strand breaks, specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here, we show that PARPis modulate immune reposes, which contribute to their therapeutic effects independent of BRCA1/2 mutations. The mechanism underlying this PARPi-induced reprogramming of anti-tumor microenvironment involves a promoted accumulation of cytosolic DNA fragments due to unresolved DNA lesions. This in turn activates the DNA sensing cGAS-STING pathway and stimulates production of type I interferons. Ultimately, these events promote PARPi-induced antitumor immunity independent of BRCAness, which can be further enhanced by immune checkpoint blockade. Our results may provide a mechanistic rationale for using PARPis as immunomodulatory agents to harness therapeutic efficacy of immune checkpoint blockade.


1996 ◽  
pp. 223-250 ◽  
Author(s):  
Richard A. Rudick ◽  
William Sibley ◽  
Luca Durelli

PLoS ONE ◽  
2012 ◽  
Vol 7 (6) ◽  
pp. e35927 ◽  
Author(s):  
Finn Sellebjerg ◽  
Martin Krakauer ◽  
Signe Limborg ◽  
Dan Hesse ◽  
Henrik Lund ◽  
...  

Reproduction ◽  
2001 ◽  
pp. 41-49 ◽  
Author(s):  
KJ Demmers ◽  
K Derecka ◽  
A Flint

The maternal recognition of pregnancy in ruminants requires the production of interferons by the preimplantation blastocyst. These proteins, the trophoblast interferons (IFN-tau), are the products of a number of similar genes, the expression of which is controlled by characteristic promoter regions. They are expressed for a short period in high concentrations, and have antiluteolytic, antiviral, antiproliferative and immunomodulatory effects, through receptors on the endometrial epithelium. The antiluteolytic effects of IFN-tau result from inhibition of endometrial expression of the oxytocin receptor, through which circulating oxytocin stimulates episodic prostaglandin F2a production. Some of the properties of IFN-tau differ from those of other type I interferons, and they may have novel therapeutic effects. Because of their central role in early gestation, these proteins have excited the interest of reproductive physiologists. However, their other properties, and the fact that their expression is controlled so precisely, have made them of interest to a wide range of biologists.


1997 ◽  
Vol 149 (1) ◽  
pp. 87-93 ◽  
Author(s):  
Klaus-Peter Wandinger ◽  
Karl Wessel ◽  
Petra Neustock ◽  
Aja Siekhaus ◽  
Holger Kirchner

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