Regulation of PD-L1 expression in K-ras-driven cancers through ROS-mediated FGFR1 signaling
Christophe Glorieux,
Xiaojun Xia,
Yong-Qiao He,
Yumin Hu,
Kelly Cremer,
Annie Robert,
Junchen Liu,
Fen Wang,
Jianhua Ling,
Paul J. Chiao,
Peng Huang
Affiliations
Christophe Glorieux
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China; Corresponding author. Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, China.
Xiaojun Xia
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
Yong-Qiao He
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
Yumin Hu
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
Kelly Cremer
Pôle Epidémiologie et Biostatistique, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, 1200, Belgium
Annie Robert
Pôle Epidémiologie et Biostatistique, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, 1200, Belgium
Junchen Liu
Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston TX, 77030, Texas, USA
Fen Wang
Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston TX, 77030, Texas, USA
Jianhua Ling
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston TX, 77030, Texas, USA
Paul J. Chiao
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston TX, 77030, Texas, USA
Peng Huang
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China; Corresponding author.
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.
