1. Academic Validation
  2. Isothiocyanates attenuate immune checkpoint blockage therapy in gastric cancer via induction of PD-L1 expression

Isothiocyanates attenuate immune checkpoint blockage therapy in gastric cancer via induction of PD-L1 expression

  • J Nutr Biochem. 2022 Nov 23;109226. doi: 10.1016/j.jnutbio.2022.109226.
Qi Zhang 1 Wanshuang Cao 2 Chenying Yang 3 Lixia Hong 4 Shanshan Geng 5 Hongyu Han 6 Caiyun Zhong 7
Affiliations

Affiliations

  • 1 Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Department of Public Health, School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210046, China. Electronic address: qizhang3036@njmu.edu.cn.
  • 2 Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: caowans@njmu.edu.cn.
  • 3 Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: yangchenying@njmu.edu.cn.
  • 4 Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: honglixia@njmu.edu.cn.
  • 5 Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: gss9814@njmu.edu.cn.
  • 6 Department of Clinical Nutrition, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. Electronic address: hanhy@sysucc.org.cn.
  • 7 Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: cyzhong@njmu.edu.cn.
Abstract

The PD-1/PD-L1 immune checkpoint blockade therapy has shown revolutionary efficacy in the treatment of multiple cancers including gastric Cancer. Isothiocyanates play important roles in Cancer cell suppression and immunomodulation. However, the effects of isothiocyanates on immune checkpoint inhibitors are poorly understood in gastric Cancer. The influence of three major isothiocyanates (sulforaphane, phenylethyl isothiocyanate and benzyl isothiocyanate) on gastric Cancer cell growth and PD-L1 expression was investigated. Syngeneic mouse models were administered by isothiocyanates and anti-PD-L1 monoclonal antibody, and the anti-tumor effects were assessed. The expression of PD-L1, proportion of lymphocytes and serum cytokine levels were detected to explore the underlying mechanisms. We found that PD-L1 expression was significantly induced by isothiocyanates which was associated with TAp63α up-regulation. We further revealed that TAp63α promoted PD-L1 through transcriptional activation. Combination treatment of isothiocyanates and anti-PD-L1 therapy weakened the sensitivity of gastric Cancer cells to anti-PD-L1 drug. Moreover, in vivo studies illustrated that the interference effects of isothiocyanates on anti-PD-L1 antibody were related to PD-L1 expression and decreased infiltrating T lymphocytes in tumor bearing mouse hosts. Our findings provide novel insights as isothiocyanates could interfere with the successful application of immunotherapy in gastric Cancer.

Keywords

Gastric cancer; Intervention; Isothiocyanates; PD-L1; TAp63α.

Figures
Products