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

Qing Li, Zhiwei Zhou, Jia Lu, Hao Luo, Shu Nan Wang, Yu Peng, Meng Sheng Deng, Guan Bin Song, Jian Min Wang, Xi Wei, Dong Wang, Kenneth D. Westover, Cheng Xiong Xu

Research output: Contribution to journalArticlepeer-review

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-L1P146R in 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.

Original languageEnglish (US)
JournalMolecular Therapy
DOIs
StateAccepted/In press - 2021

Keywords

  • gastric cancer
  • immunotherapy
  • PD-1/PD-L1
  • polymorphism

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Fingerprint

Dive into the research topics of 'PD-L1<sup>P146R</sup> is prognostic and a negative predictor of response to immunotherapy in gastric cancer'. Together they form a unique fingerprint.

Cite this