PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness.
Cancer Res
; 79(2): 311-319, 2019 01 15.
Article
em En
| MEDLINE
| ID: mdl-30482774
ABSTRACT
PARP inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2-mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of ssDNA 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 PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations. PARPi promoted accumulation of cytosolic DNA fragments because of unresolved DNA lesions, which in turn activated the DNA-sensing cGAS-STING pathway and stimulated production of type I IFNs to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade. SIGNIFICANCE:
This work uncovers the mechanism behind the clinical efficacy of PARPi in patients with both BRCA-wild-type and BRCA-mutant tumors and provides a rationale for combining PARPi with immunotherapy in patients with cancer.
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1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ovarianas
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Neoplasias Colorretais
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Protocolos de Quimioterapia Combinada Antineoplásica
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Antígeno B7-H1
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Inibidores de Poli(ADP-Ribose) Polimerases
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Proteínas de Membrana
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Anticorpos
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article