PD-L1 sustains chronic, cancer cell-intrinsic responses to type I interferon, enhancing resistance to DNA damage.
Proc Natl Acad Sci U S A
; 118(47)2021 11 23.
Article
em En
| MEDLINE
| ID: mdl-34799452
ABSTRACT
Programmed death ligand 1 (PD-L1), an immune-checkpoint protein expressed on cancer cells, also functions independently of the immune system. We found that PD-L1 inhibits the killing of cancer cells in response to DNA damage in an immune-independent manner by suppressing their acute response to type I interferon (IFN; IFN-I). In addition, PD-L1 plays a critical role in sustaining high levels of constitutive expression in cancer cells of a subset of IFN-induced genes, the IFN-related DNA damage resistance signature (IRDS) which, paradoxically, protects cancer cells. The cyclic GMP-AMP synthase-stimulator of the IFN genes (cGAS-STING) pathway is constitutively activated in a subset of cancer cells in the presence of high levels of PD-L1, thus leading to a constitutive, low level of IFN-ß expression, which in turn increases IRDS expression. The constitutive low level of IFN-ß expression is critical for the survival of cancer cells addicted to self-produced IFN-ß. Our study reveals immune-independent functions of PD-L1 that inhibit cytotoxic acute responses to IFN-I and promote protective IRDS expression by supporting protective chronic IFN-I responses, both of which enhance the resistance of cancer cells to DNA damage.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
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Interferon Tipo I
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Antígeno B7-H1
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article