Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA

Coelho, M. A., S. de Carné Trécesson, S. Rana, D. Zecchin, C. Moore, M. Molina-Arcas, P. East, B. Spencer-Dene, E. Nye and K. Barnouin (2017). Immunity 47(6): 1083-1099. e1086.
 

Speaker: Man-Ling Chu (朱曼菱)         Time: 13:10 ~ 14:00, May 16, 2018

Commentator: Dr. Hung-Chi Cheng (鄭宏祺 老師)         Place: Room 601

Abstract:

Programmed death-ligand 1 (PD-L1) upregulated in many cancers is an immunorepressive protein. Tumor cells express PD-L1 to evade the host immunity. Blockade of PD-L1 becomes to the therapeutic target for many anti-cancer drugs. However, few patients respond well to the anti-PD-L1 treatment. Therefore, identification of reliable biomarkers to predict patients’ responses becomes an important task. The clinical trial of anti-PD-L1 antibody “nivolumab” shows a correlation between PD-L1 expression and treatment response in non-squamous non-small cell lung cancer (NSCLC) patients. Especially, the patients with KRas mutations showed good response after anti-PD-L1 antibody treatment compared to the wild–type KRas patients(1). It implies that the expression of PD-L1 may be regulated by Ras signaling. The 3’UTR of PD-L1 is genetically mutated in many cancers and correlates with high PD-L1 expression(2). AU-rich element binding protein tristeraprolin (TTP) negatively regulates PD-L1 expression by the mRNA decay machinery. Ras signaling increases PD-L1 mRNA stability through AU-rich element in the 3’UTR. The phosphorylation of s52 and s178 residues of TTP is crucial for TTP activity, which was phosphorylated by MAPKAP kinase-2 (MK2) from patient-derived samples. MK2 is a downstream molecule of Ras signaling and reduces TTP-mediated PD-L1 mRNA-decaying activity. In summary, Ras signaling pathway positively correlates with PD-L1 expression through inactivation of TTP by Ras-MK2-phosphorylation inhibiting TTP activity.

References:

1.     Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N. Engl. J. Med. 2015;373(2):123-35.

2.     Kataoka K, Shiraishi Y, Takeda Y, Sakata S, Matsumoto M, Nagano S, et al. Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers. Nature. 2016;534(7607):402.