Tryptophan metabolism and disposition in cancer biology and immunotherapy

Biosci Rep. 2022 Nov 30;42(11):BSR20221682. doi: 10.1042/BSR20221682.

Abstract

Tumours utilise tryptophan (Trp) and its metabolites to promote their growth and evade host defences. They recruit Trp through up-regulation of Trp transporters, and up-regulate key enzymes of Trp degradation and down-regulate others. Thus, Trp 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenase 1 (IDO1), IDO2, N'-formylkynurenine formamidase (FAMID) and Kyn aminotransferase 1 (KAT1) are all up-regulated in many cancer types, whereas Kyn monooxygenase (KMO), kynureninase (KYNU), 2-amino-3-carboxymuconic acid-6-semialdehyde decarboxylase (ACMSD) and quinolinate phosphoribosyltransferase (QPRT) are up-regulated in a few, but down-regulated in many, cancers. This results in accumulation of the aryl hydrocarbon receptor (AhR) ligand kynurenic acid and in depriving the host of NAD+ by blocking its synthesis from quinolinic acid. The host loses more NAD+ by up-regulation of the NAD+-consuming poly (ADP-ribose) polymerases (PARPs) and the protein acetylaters SIRTs. The nicotinamide arising from PARP and SIRT activation can be recycled in tumours to NAD+ by the up-regulated key enzymes of the salvage pathway. Up-regulation of the Trp transporters SLC1A5 and SLC7A5 is associated mostly with that of TDO2 = FAMID > KAT1 > IDO2 > IDO1. Tumours down-regulate enzymes of serotonin synthesis, thereby removing competition for Trp from the serotonin pathway. Strategies for combating tumoral immune escape could involve inhibition of Trp transport into tumours, inhibition of TDO and IDOs, inhibition of FAMID, inhibition of KAT and KYNU, inhibition of NMPRT and NMNAT, inhibition of the AhR, IL-4I1, PARPs and SIRTs, and by decreasing plasma free Trp availability to tumours by albumin infusion or antilipolytic agents and inhibition of glucocorticoid induction of TDO by glucocorticoid antagonism.

Keywords: 3-dioxygenase; 3dioxygenase; Aryl hydrocarbon receptor; indoleamine 2; kynurenic acid; kynurenine pathway; tryptophan 2; tumor immune escape.

MeSH terms

  • Amino Acid Transport System ASC
  • Biology
  • Glucocorticoids
  • Humans
  • Immunotherapy
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Minor Histocompatibility Antigens
  • NAD / metabolism
  • Neoplasms* / metabolism
  • Neoplasms* / therapy
  • Serotonin
  • Sirtuins* / metabolism
  • Tryptophan / metabolism

Substances

  • Tryptophan
  • NAD
  • Glucocorticoids
  • Serotonin
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Sirtuins
  • SLC1A5 protein, human
  • Minor Histocompatibility Antigens
  • Amino Acid Transport System ASC