Tobacco carcinogen induces tryptophan metabolism and immune suppression via induction of indoleamine 2,3-dioxygenase 1

Signal Transduct Target Ther. 2022 Sep 7;7(1):311. doi: 10.1038/s41392-022-01127-3.

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1), the enzyme that catabolizes tryptophan (Trp) metabolism to promote regulatory T cells (Tregs) and suppress CD8+ T cells, is regulated by several intrinsic signaling pathways. Here, we found that tobacco smoke, a major public health concern that kills 8 million people each year worldwide, induced IDO1 in normal and malignant lung epithelial cells in vitro and in vivo. The carcinogen nicotine-derived nitrosaminoketone (NNK) was the tobacco compound that upregulated IDO1 via activation of the transcription factor c-Jun, which has a binding site for the IDO1 promoter. The NNK receptor α7 nicotinic acetylcholine receptor (α7nAChR) was required for NNK-induced c-Jun activation and IDO1 upregulation. In A/J mice, NNK reduced CD8+ T cells and increased Tregs. Clinically, smoker patients with non-small-cell lung cancer (NSCLC) exhibited high IDO1 levels and low Trp/kynurenine (Kyn) ratios. In NSCLC patients, smokers with lower IDO1 responded better to anti-PD1 antibody treatment than those with higher IDO1. These data indicate that tobacco smoke induces IDO1 to catabolize Trp metabolism and immune suppression to promote carcinogenesis, and lower IDO1 might be a potential biomarker for anti-PD1 antibodies in smoker patients, whereas IDO1-high smoker patients might benefit from IDO1 inhibitors in combination with anti-PD1 antibodies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / metabolism
  • Carcinogens / toxicity
  • Carcinoma, Non-Small-Cell Lung*
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Lung Neoplasms* / chemically induced
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Mice
  • Nicotiana / metabolism
  • Tobacco Smoke Pollution*
  • Tryptophan

Substances

  • Carcinogens
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Tobacco Smoke Pollution
  • Tryptophan