PMID- 30940655
OWN - NLM
STAT- Publisher
LR  - 20190522
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
DP  - 2019 Apr 2
TI  - Regorafenib Promotes Antitumor Immunity via Inhibiting PD-L1 and IDO1 Expression 
      in Melanoma.
LID - 10.1158/1078-0432.CCR-18-2840 [doi]
AB  - Purpose: Immune checkpoint blockade (ICB) therapy induces durable tumor
      regressions in a minority of patients with cancer. In this study, we aimed to
      identify kinase inhibitors that were capable of increasing the antimelanoma
      immunity.Experimental Design: Flow cytometry-based screening was performed to
      identify kinase inhibitors that can block the IFNgamma-induced PD-L1 expression
      in melanoma cells. The pharmacologic activities of regorafenib alone or in
      combination with immunotherapy in vitro and in vivo were determined. The
      mechanisms of regorafenib were explored and analyzed in melanoma patients treated
      with or without anti-PD-1 using The Gene Expression Omnibus (GEO) and The Cancer 
      Genome Atlas (TCGA) datasets.Result: Through screening of a kinase inhibitor
      library, we found approximately 20 agents that caused more than half reduction of
      cell surface PD-L1 level, and regorafenib was one of the most potent agents.
      Furthermore, our results showed that regorafenib, in vitro and in vivo, strongly 
      promoted the antitumor efficacy when combined with IFNgamma or ICB. By targeting 
      the RET-Src axis, regorafenib potently inhibited JAK1/2-STAT1 and MAPK signaling 
      and subsequently attenuated the IFNgamma-induced PD-L1 and IDO1 expression
      without affecting MHC-I expression much. Moreover, RET and Src co-high expression
      was an independent unfavorable prognosis factor in melanoma patients with or
      without ICB through inhibiting the antitumor immune response.Conclusions: Our
      data unveiled a new mechanism of alleviating IFNgamma-induced PD-L1 and IDO1
      expression and provided a rationale to explore a novel combination of ICB with
      regorafenib clinically, especially in melanoma with RET/Src axis activation.
CI  - (c)2019 American Association for Cancer Research.
FAU - Wu, Rui-Yan
AU  - Wu RY
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Kong, Peng-Fei
AU  - Kong PF
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Xia, Liang-Ping
AU  - Xia LP
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
AD  - Department of the VIP Region, Sun Yat-sen University Cancer Center, Guangzhou,
      China.
FAU - Huang, Yun
AU  - Huang Y
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Li, Zhi-Ling
AU  - Li ZL
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Tang, Yun-Yun
AU  - Tang YY
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Chen, Yu-Hong
AU  - Chen YH
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Li, Xuan
AU  - Li X
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Senthilkumar, Ravichandran
AU  - Senthilkumar R
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Zhang, Hai-Liang
AU  - Zhang HL
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Sun, Ting
AU  - Sun T
AD  - Key Clinical Laboratory of Henan Province, Department of Clinical Laboratory, The
      First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
FAU - Xu, Xue-Lian
AU  - Xu XL
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Yu, Yan
AU  - Yu Y
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Mai, Jia
AU  - Mai J
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Peng, Xiao-Dan
AU  - Peng XD
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Yang, Dong
AU  - Yang D
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Zhou, Li-Huan
AU  - Zhou LH
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Feng, Gong-Kan
AU  - Feng GK
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Deng, Rong
AU  - Deng R
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
      zhuxfeng@mail.sysu.edu.cn dengrong@sysucc.org.cn.
FAU - Zhu, Xiao-Feng
AU  - Zhu XF
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma
      Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
      zhuxfeng@mail.sysu.edu.cn dengrong@sysucc.org.cn.
LA  - eng
PT  - Journal Article
DEP - 20190402
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for
      Cancer Research
JID - 9502500
EDAT- 2019/04/04 06:00
MHDA- 2019/04/04 06:00
CRDT- 2019/04/04 06:00
PHST- 2018/09/07 00:00 [received]
PHST- 2019/01/26 00:00 [revised]
PHST- 2019/03/26 00:00 [accepted]
PHST- 2019/04/04 06:00 [pubmed]
PHST- 2019/04/04 06:00 [medline]
PHST- 2019/04/04 06:00 [entrez]
AID - 1078-0432.CCR-18-2840 [pii]
AID - 10.1158/1078-0432.CCR-18-2840 [doi]
PST - aheadofprint
SO  - Clin Cancer Res. 2019 Apr 2. pii: 1078-0432.CCR-18-2840. doi:
      10.1158/1078-0432.CCR-18-2840.