2. Academic Validation
  3. Pleckstrin-2 promotes tumour immune escape from NK cells by activating the MT1-MMP-MICA signalling axis in gastric cancer

Pleckstrin-2 promotes tumour immune escape from NK cells by activating the MT1-MMP-MICA signalling axis in gastric cancer

  • Cancer Lett. 2023 Aug 15;572:216351. doi: 10.1016/j.canlet.2023.216351.
Deli Mao 1,  Zhijun Zhou 2,  Hengxing Chen 1,  Xinran Liu 1,  Dongsheng Li 1,  Xiancong Chen 1,  Yulong He 3,  Mingyang Liu 4,  Changhua Zhang 5
Affiliations

Affiliations

  • 1 Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China.
  • 2 Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, United States.
  • 3 Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Department of Gastrointestinal Surgery of the First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China.
  • 4 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China. Electronic address: liumy@cicams.ac.cn.
  • 5 Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, China. Electronic address: zhchangh@mail.sysu.edu.cn.
PMID: 37591356 DOI: 10.1016/j.canlet.2023.216351
Abstract

Immune escape is a major challenge in tumour immunotherapy. Pleckstrin-2(PLEK2) plays a critical role in tumour progression, but its role in immune escape in gastric Cancer (GC) remains uncharacterized. RNA sequencing was used to explore the differentially expressed genes in a GC cell line that was resistant to the antitumor effect of Natural killer (NK) cells. Apoptosis and the expression of IFN-γ and TNF-α were detected by flow cytometry (FCM). PLEK2 expression was examined by Western blotting and immunohistochemistry (IHC). PLEK2 was upregulated in MGC803R cells that were resistant to the antitumor effect of NK cells. PLEK2 knockout increased the sensitivity of GC cells to NK cell killing. PLEK2 expression was negatively correlated with MICA and positively correlated with MT1-MMP expression both in vitro and in vivo. PLEK2 promoted Sp1 phosphorylation through the PI3K-AKT pathway, thereby upregulating MT1-MMP expression, which ultimately led to MICA shedding. In mouse xenograft models, PLEK2 knockout inhibited intraperitoneal metastasis of GC cells and promoted NK cell infiltration. In summary, PLEK2 suppressed NK cell immune surveillance by promoting MICA shedding, which serves as a potential therapeutic target for GC.

Keywords

Gastric cancer; Immune evasion; MICA; NK cells; PLEK2.

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