Regulation of PD-L1 expression in K-ras-driven cancers through ROS-mediated FGFR1 signaling.
Redox Biol
; 38: 101780, 2021 01.
Article
in En
| MEDLINE
| ID: mdl-33171331
ABSTRACT
K-ras mutations are major genetic events that drive cancer development associated with aggressive malignant phenotypes, while expression of the immune checkpoint molecule PD-L1 plays a key role in cancer evasion of the immune surveillance that also profoundly affects the patient outcome. However, the relationship between K-ras oncogenic signal and PD-L1 expressions as an important area that requires further investigation. Using both in vitro and in vivo experimental models of K-ras-driven cancer, we found that oncogenic K-ras significantly enhanced PD-L1 expression through a redox-mediated mechanism. Activation of K-rasG12V promoted ROS generation and induced FGFR1 expression, leading to a significant upregulation of PD-L1. We further showed that exogenous ROS such as hydrogen peroxide alone was sufficient to activate FGFR1 and induce PD-L1, while antioxidants could largely abrogate PD-L1 expression in K-ras mutant cells, indicating a critical role of redox regulation. Importantly, genetic knockout of FGFR1 led to a decrease in PD-L1 expression, and impaired tumor growth in vivo due to a significant increase of T cell infiltration in the tumor tissues and thus enhanced T-cell-mediated tumor suppression. Our study has identified a novel mechanism by which K-ras promotes PD-L1 expression, and suggests that modulation of ROS or inhibition of the FGFR1 pathway could be a novel strategy to abrogate PD-L1-mediated immunosuppression and thus potentially improve the efficacy of immunotherapy in K-ras-driven cancers.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Proto-Oncogene Proteins p21(ras)
/
B7-H1 Antigen
/
Neoplasms
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Redox Biol
Year:
2021
Type:
Article