Enhanced Acid Sphingomyelinase Activity Drives Immune Evasion and Tumor Growth in Non-Small Cell Lung Carcinoma

Cancer Res. 2017 Nov 1;77(21):5963-5976. doi: 10.1158/0008-5472.CAN-16-3313. Epub 2017 Sep 7.

Abstract

The lipid hydrolase enzyme acid sphingomyelinase (ASM) is required for the conversion of the lipid cell membrane component sphingomyelin into ceramide. In cancer cells, ASM-mediated ceramide production is important for apoptosis, cell proliferation, and immune modulation, highlighting ASM as a potential multimodal therapeutic target. In this study, we demonstrate elevated ASM activity in the lung tumor environment and blood serum of patients with non-small cell lung cancer (NSCLC). RNAi-mediated attenuation of SMPD1 in human NSCLC cells rendered them resistant to serum starvation-induced apoptosis. In a murine model of lung adenocarcinoma, ASM deficiency reduced tumor development in a manner associated with significant enhancement of Th1-mediated and cytotoxic T-cell-mediated antitumor immunity. Our findings indicate that targeting ASM in NSCLC can act by tumor cell-intrinsic and -extrinsic mechanisms to suppress tumor cell growth, most notably by enabling an effective antitumor immune response by the host. Cancer Res; 77(21); 5963-76. ©2017 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Apoptosis / genetics
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Ceramides / blood
  • Ceramides / metabolism
  • Humans
  • Immune Evasion*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mice
  • RNA Interference
  • Sphingomyelin Phosphodiesterase / blood
  • Sphingomyelin Phosphodiesterase / genetics
  • Sphingomyelin Phosphodiesterase / metabolism*
  • Sphingomyelins / blood
  • Sphingomyelins / metabolism
  • Tandem Mass Spectrometry
  • Tumor Burden

Substances

  • Ceramides
  • Sphingomyelins
  • Sphingomyelin Phosphodiesterase