SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion.
Cell
; 187(4): 861-881.e32, 2024 Feb 15.
Article
en En
| MEDLINE
| ID: mdl-38301646
ABSTRACT
Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 limits endogenous DNA damage, thereby suppressing cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a PD-L1 transcriptional regulatory element, thereby promoting PD-L1 expression in cancer cells. SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a promising target for cancer immunotherapy.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
ADN Helicasas
/
Escape del Tumor
/
Antígeno B7-H1
/
Inmunidad Innata
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Melanoma
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Cell
Año:
2024
Tipo del documento:
Article