Mevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA.
10.1016/j.apsb.2023.04.002
- Author:
Wenxin ZHANG
1
;
Xiaohui PAN
1
;
Yanjun XU
2
;
Hongjie GUO
1
;
Mingming ZHENG
1
;
Xi CHEN
1
;
Honghai WU
1
;
Fengming LUAN
3
;
Qiaojun HE
1
;
Ling DING
1
;
Bo YANG
1
Author Information
1. Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
2. Department of Medical Thoracic Oncology, the Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Chinese Academy of Sciences, Hangzhou 310022, China.
3. Department of Gastrointestinal Surgery, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou 310009, China.
- Publication Type:Journal Article
- Keywords:
HuR;
Immune checkpoint blockade;
Metabolites;
Mevalonate;
NSCLC;
PD-L1;
mRNA stability
- From:
Acta Pharmaceutica Sinica B
2023;13(6):2585-2600
- CountryChina
- Language:English
-
Abstract:
Mevalonate metabolism plays an important role in regulating tumor growth and progression; however, its role in immune evasion and immune checkpoint modulation remains unclear. Here, we found that non-small cell lung cancer (NSCLC) patients with higher plasma mevalonate response better to anti-PD-(L)1 therapy, as indicated by prolonged progression-free survival and overall survival. Plasma mevalonate levels were positively correlated with programmed death ligand-1 (PD-L1) expression in tumor tissues. In NSCLC cell lines and patient-derived cells, supplementation of mevalonate significantly up-regulated the expression of PD-L1, whereas deprivation of mevalonate reduced PD-L1 expression. Mevalonate increased CD274 mRNA level but did not affect CD274 transcription. Further, we confirmed that mevalonate improved CD274 mRNA stability. Mevalonate promoted the affinity of the AU-rich element-binding protein HuR to the 3'-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA. By in vivo study, we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1, increased the infiltration of CD8+ T cells, and improved cytotoxic function of T cells. Collectively, our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody, and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.
