2. Academic Validation
  3. PD-L1P146R is prognostic and a negative predictor of response to immunotherapy in gastric cancer

PD-L1P146R is prognostic and a negative predictor of response to immunotherapy in gastric cancer

  • Mol Ther. 2022 Feb 2;30(2):621-631. doi: 10.1016/j.ymthe.2021.09.013.
Qing Li 1,  Zhi-Wei Zhou 2,  Jia Lu 2,  Hao Luo 3,  Shu-Nan Wang 4,  Yu Peng 5,  Meng-Sheng Deng 6,  Guan-Bin Song 7,  Jian-Min Wang 6,  Xi Wei 8,  Dong Wang 9,  Kenneth D Westover 10,  Cheng-Xiong Xu 11
Affiliations

Affiliations

  • 1 Cancer Center, Daping Hospital, Army Medical University, Chongqing 400042, China; School of Medicine, Chongqing University, Chongqing 400030, China.
  • 2 Department of Radiation Oncology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3 Cancer Center, Daping Hospital, Army Medical University, Chongqing 400042, China; Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China.
  • 4 Department of Radiology, Daping Hospital, Army Medical University, Chongqing 400042, China.
  • 5 Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 6 State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China.
  • 7 Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China.
  • 8 Department of Diagnostic Ultrasound, Tianjin Medical University Cancer Institute and Hospital, Tianjin 330006, China.
  • 9 Cancer Center, Daping Hospital, Army Medical University, Chongqing 400042, China. Electronic address: dongwang64@hotmail.com.
  • 10 Department of Radiation Oncology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: Kenneth.westover@utsouthwestern.edu.
  • 11 Cancer Center, Daping Hospital, Army Medical University, Chongqing 400042, China; School of Medicine, Chongqing University, Chongqing 400030, China. Electronic address: xuchengxiong@cqu.edu.cn.
PMID: 34547468 DOI: 10.1016/j.ymthe.2021.09.013
Abstract

Cancer cells evade immune detection via programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) interactions that inactivate T cells. PD-1/PD-L1 blockade has become an important therapy in the anti-cancer armamentarium. However, some patients do not benefit from PD-1/PD-L1 blockade despite expressing PD-L1. Here, we screened 101 gastric Cancer (GC) patients at diagnosis and 141 healthy control subjects and reported one such subpopulation of GC patients with rs17718883 polymorphism in PD-L1, resulting in a nonsense P146R mutation. We detected rs17718883 in 44% of healthy control subjects, and rs17718883 was associated with a low susceptibility to GC and better prognosis in GC patients. Structural analysis suggests that the mutation weakens the PD-1:PD-L1 interaction. This was supported by co-culture experiments of T cells, with GC cells showing that the P146R substitution results in interferon (IFN)-γ secretion by T cells and enables T cells to suppress GC cell growth. Similar results with animal gastric tumor models were obtained in vivo. PD-1 monoclonal antibody treatment did not enhance the inhibitory effect of T cells on GC cells expressing PD-L1P146Rin vitro or in vivo. This study suggests that rs17718883 is common and may be used as a biomarker for exclusion from PD-1/PD-L1 blockade therapy.

Keywords

PD-1/PD-L1; gastric cancer; immunotherapy; polymorphism.

Figures
Products
Inhibitors & Agonists
Other Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z