PD-L1 sustains chronic, cancer cell-intrinsic responses to type I interferon, enhancing resistance to DNA damage
| Autor: | Elise G. Holvey-Bates, HyeonJoo Cheon, Daniel J. McGrail, George R. Stark |
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| Rok vydání: | 2021 |
| Předmět: |
Lung Neoplasms
DNA damage B7-H1 Antigen Interferon-gamma Immune system Interferon PD-L1 Cell Line Tumor medicine Tumor Microenvironment Cytotoxic T cell Humans Gene Multidisciplinary biology Chemistry Interferon-beta Biological Sciences Ligand (biochemistry) Nucleotidyltransferases Gene Expression Regulation Neoplastic Cancer cell Interferon Type I Cancer research biology.protein medicine.drug DNA Damage Signal Transduction |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 |
| Popis: | 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-β expression, which in turn increases IRDS expression. The constitutive low level of IFN-β expression is critical for the survival of cancer cells addicted to self-produced IFN-β. 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. |
| Databáze: | OpenAIRE |
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