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Can IDO activity predict primary resistance to anti-PD-1 treatment in NSCLC?

Andrea Botticelli1, Bruna Cerbelli2, Luana Lionetto3

  • 1Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Via di Grottarossa 1035-1037, 00189, Rome, Italy. andreabotticelli@hotmail.it.

Journal of Translational Medicine
|August 8, 2018
PubMed
Abstract

Insights

Higher indoleamine 2,3-dioxygenase (IDO) activity, indicated by an increased kynurenine/tryptophan (kyn/trp) ratio, predicts resistance to anti-PD-1 immunotherapy in non-small cell lung cancer (NSCLC). This suggests combining anti-PD-1 therapy with IDO inhibitors may benefit patients with high IDO activity.

Area of Science:

  • Oncology
  • Immunology
  • Biochemistry

Background:

  • Immune checkpoint inhibitors (ICIs) like anti-PD-1 have advanced non-small cell lung cancer (NSCLC) treatment, yet many patients exhibit resistance.
  • Indoleamine 2,3-dioxygenase (IDO) activity is implicated in creating an immunosuppressive tumor microenvironment, potentially driving resistance to anti-PD-1 therapy.

Purpose of the Study:

  • To investigate the association between IDO activity, measured by the kynurenine/tryptophan (kyn/trp) ratio, and treatment response in NSCLC patients receiving anti-PD-1 therapy.
  • To determine if pre-treatment IDO activity can predict progression-free survival (PFS) and overall survival (OS).

Main Methods:

  • Serum tryptophan (trp) and kynurenine (kyn) levels were quantified using high-performance liquid chromatography tandem mass spectrometry in NSCLC patients undergoing second-line nivolumab treatment.
  • IDO activity was calculated as the kyn/trp ratio, and its correlation with early progression, clinical factors, PFS, and OS was analyzed.

Main Results:

  • A higher kyn/trp ratio and quinolinic acid concentration were significantly correlated with early progression (p=0.017 and p=0.005, respectively).
  • Patients with lower kyn/trp ratios experienced significantly longer PFS (not reached vs. 3 months; HR: 0.3; p=0.018) and OS (not reached vs. 3 months; HR: 0.18; p=0.0005).

Conclusions:

  • IDO activity, reflected by the kyn/trp ratio, is a potential biomarker for predicting response to anti-PD-1 immunotherapy in NSCLC.
  • Elevated IDO activity may indicate resistance to anti-PD-1 therapy, suggesting a therapeutic strategy involving combination anti-PD-1 and IDO inhibitors for patients with high kyn/trp ratios.
Keywords:
Anti-PD-1IDOImmunotherapyKynurenineNivolumab

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