Z-DNA enhances immunotherapy by triggering death of inflammatory cancer-associated fibroblasts.
J Immunother Cancer
; 10(11)2022 11.
Article
em En
| MEDLINE
| ID: mdl-36450382
ABSTRACT
Cancer-associated fibroblasts (CAFs) are a heterogeneous population of cells. At one end of the spectrum are alpha-smooth muscle actin expressing myoCAFs (myofibroblast CAFs) and at the other end are the interferon (IFN) and Janus Kinase/Signal Transducer and Activator of Transcription responsive iCAFs (inflammatory CAFs). Both types of CAFs promote tumor growth. While myoCAFs foster immune exclusion and limit tumor spread, iCAFs create a highly immunosuppressive environment and foster the seeding of distant metastases. However, iCAFs also represent a tumor vulnerability. They are competent to undergo necroptosis, a highly immunogenic form of cell death that is triggered when Z-DNA or Z-RNA (collectively called ZNA) is sensed by the IFN-induced ZNA binding protein 1 (ZBP1). The sequestering of ZNA ligands by the p150 isoform of the double-stranded RNA-specific deaminase ADAR1 protects iCAFs from cell death. ZBP1-dependent necroptosis in iCAFs can be triggered by administering an orally available small molecule that generates sufficient amounts of ZNA to bypass ADAR1 inhibition. The therapeutic approach of targeting Z-prone sequences (called flipons) is agnostic to the mutations driving cancer progression. By exploiting the tumor vulnerability posed by expression of ZBP1-dependent immunogenic cell death pathways in iCAFs, flipon therapeutics offer new hope for improved clinical outcomes.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA Forma Z
/
Fibroblastos Associados a Câncer
/
Neoplasias
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
J Immunother Cancer
Ano de publicação:
2022
Tipo de documento:
Article