Rocaglamide enhances NK cell-mediated killing of non-small cell lung cancer cells by inhibiting autophagy

Autophagy. 2018;14(10):1831-1844. doi: 10.1080/15548627.2018.1489946. Epub 2018 Aug 17.

Abstract

Targeting macroautophagy/autophagy is a novel strategy in cancer immunotherapy. In the present study, we showed that the natural product rocaglamide (RocA) enhanced natural killer (NK) cell-mediated lysis of non-small cell lung cancer (NSCLC) cells in vitro and tumor regression in vivo. Moreover, this effect was not related to the NK cell recognition of target cells or expressions of death receptors. Instead, RocA inhibited autophagy and restored the level of NK cell-derived GZMB (granzyme B) in NSCLC cells, therefore increasing their susceptibility to NK cell-mediated killing. In addition, we further identified that the target of RocA was ULK1 (unc-51 like autophagy activating kinase 1) that is required for autophagy initiation. Using firefly luciferase containing the 5´ untranslated region of ULK1, we found that RocA inhibited the protein translation of ULK1 in a sequence-specific manner. Taken together, RocA could block autophagic immune resistance to NK cell-mediated killing, and our data suggested that RocA was a promising therapeutic candidate in NK cell-based cancer immunotherapy.

Keywords: Autophagy; cancer immunotherapy; immune resistance; natural killer cells; non-small cell lung cancer; rocaglamide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy* / drug effects
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Benzofurans / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / immunology*
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Degranulation / drug effects
  • Granzymes / metabolism
  • Humans
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / physiology
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / pathology*
  • Male
  • Mice, Inbred C57BL
  • Mice, SCID
  • Models, Biological
  • Protein Biosynthesis
  • Receptors, Death Domain / metabolism

Substances

  • Benzofurans
  • Receptors, Death Domain
  • rocaglamide
  • Autophagy-Related Protein-1 Homolog
  • Granzymes

Grants and funding

This study was supported by National Natural Science Foundation of China (81473237), the Shanghai Foundation for Development of Science and Technology (14431902600), the budget project of Shanghai Municipal Education Commission (2016YSN01), the foundation for Shanghai Municipal Commission of Health and Family Planning (20154Y0167) and the Interdisciplinary Project of “Clinical Immunology of Traditional Chinese Medicine” in Shanghai (30304113598).