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bioRxiv · 10.1101/318980

PARPi triggers STING-dependent immune response and enhances therapeutic efficacy of immune checkpoint blockade independent of BRCAness

Shen, J.·Zhao, W.·Ju, Z.·Wang, L.·Peng, Y.·Labrie, M.·Yap, T.·Mills, G. B.·Peng, G.
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Abstract

Poly-(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.

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Shen, J., Zhao, W., Ju, Z., Wang, L., Peng, Y., Labrie, M., Yap, T., Mills, G. B., Peng, G.. 2018-05-10. PARPi triggers STING-dependent immune response and enhances therapeutic efficacy of immune checkpoint blockade independent of BRCAness. https://doi.org/10.1101/318980

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