A Validation Study on IDO Immune Biomarkers for Survival Prediction in Non-Small Cell Lung Cancer: Radiation Dose Fractionation Effect in Early-Stage Disease

Clin Cancer Res. 2020 Jan 1;26(1):282-289. doi: 10.1158/1078-0432.CCR-19-1202. Epub 2019 Aug 30.


Purpose: We recently reported that indoleamine 2, 3-dioxygenase (IDO) activity is significantly correlated with more distant metastasis and worse survival. The present study examined whether radiotherapy (RT) dose fractionation correlates with IDO-mediated immune activity in patients with early-stage NSCLC.Methods: Patients with newly diagnosed stage I-II NSCLC treated with either conventionally fractionated 3-dimensional conformal radiotherapy (3DCRT) or stereotactic body radiotherapy (SBRT) were analyzed. Levels of two key molecules associated with the IDO immune checkpoint, serum kynurenine and the kynurenine:tryptophan ratio (K:T ratio), were measured at pre-RT, during-RT, and 3-month post-RT. The relationship between disease control outcomes [overall survival (OS), progression free survival, and local/regional/distant failure rates] and absolute levels of these markers, as well as dynamic changes in their levels during RT, was studied.

Results: Fifty-six patients (SBRT = 28, 3DCRT = 28) with early-stage NSCLC were studied. In all patients, higher kynurenine post-RT was significantly associated with worse OS ([HR, 1.25; 95% confidence interval (CI), 1.01-1.55; P = 0.044). No statistically significant differences in absolute kynurenine levels or the K:T ratio were observed in patients treated with 3DCRT or SBRT at any of the three time points. However, the absolute kynurenine levels rose significantly more post-RT in the 3DCRT patients with a median increase 0.721 ng/mL, compared to that of SBRT patients (0.115 ng/mL); P = 0.022.

Conclusions: This study validated that elevated IDO activity correlated with worse survival outcomes in patients with early-stage NSCLC treated with definitive RT. Hypofractionated SBRT may have less immunosuppressive effect than 3DCRT, as measured by IDO.

Publication types

  • Research Support, N.I.H., Extramural
  • Validation Study

MeSH terms

  • Aged
  • Biomarkers, Tumor / immunology
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Carcinoma, Non-Small-Cell Lung / mortality*
  • Carcinoma, Non-Small-Cell Lung / radiotherapy
  • Dose Fractionation, Radiation
  • Female
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
  • Kynurenine / blood
  • Lung Neoplasms / immunology
  • Lung Neoplasms / mortality*
  • Lung Neoplasms / radiotherapy
  • Male
  • Neoplasm Staging
  • Radiosurgery / methods*
  • Radiotherapy, Conformal / methods*
  • Survival Rate
  • Tryptophan / blood


  • Biomarkers, Tumor
  • IDO1 protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Kynurenine
  • Tryptophan