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

• Published in: Journal of translational medicine Vol. 16; no. 1; p. 219
• Main Authors: Botticelli, Andrea, Cerbelli, Bruna, Lionetto, Luana, Zizzari, Ilaria, Salati, Massimiliano, Pisano, Annalinda, Federica, Mazzuca, Simmaco, Maurizio, Nuti, Marianna, Marchetti, Paolo
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 06-08-2018; BioMed Central; BMC
• Subjects: Aged; Anti-PD-1; Biomarkers; Cancer therapies; Carcinoma, Non-Small-Cell Lung - blood; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - therapy; Chemotherapy; Chromatography; Development and progression; Disease Progression; Dosage and administration; Drug Resistance, Neoplasm; Drug therapy; FDA approval; Female; High performance liquid chromatography; Humans; IDO; Immunology; Immunosuppression; Immunotherapy; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Kaplan-Meier Estimate; Kynurenine; Kynurenine - blood; Lung cancer; Lung Neoplasms - blood; Lung Neoplasms - enzymology; Lung Neoplasms - therapy; Male; Mass spectrometry; Medical prognosis; Metabolism; Metabolites; Multivariate Analysis; Nivolumab; Non-small cell lung cancer; Non-small cell lung carcinoma; Patients; PD-1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Quinolinic Acid - blood; Scientific imaging; Tryptophan - blood; Kynurenine; Anti-PD-1; IDO; Immunotherapy; Nivolumab
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-018-1595-3

Immune checkpoint inhibitors have revolutionized the treatment paradigm of highly lethal malignancies like advanced non-small cell lung cancer (NSCLC), demonstrating long-term tumour control and extended patient survival. Unfortunately, only 25-30% of patients experience a durable benefit, while the vast majority demonstrate primary or acquired resistance. Recently, indoleamine 2,3-dioxygenase (IDO) activity has been proposed as a possible mechanism of resistance to anti-PD-1 treatment leading to an immunosuppressive microenvironment.
Pre-treatment serum concentrations of tryptophan (trp) and kynurenine (kyn) were measured by high-performance liquid chromatography tandem mass spectrometry in NSCLC patients treated with second-line nivolumab. The IDO activity was expressed with kyn/trp ratio. The associations between kyn/trp ratio and early progression, performance status (PS), age, sex, brain metastases, pleural effusion, progression free survival (PFS) and overall survival (OS) were analyzed using Spearman test and Mann-Whitney test.
Twenty-six NSCLC patients were included in our study; 14 of them (54%) presented early progression (< 3 months) to nivolumab treatment. The median value of kyn/trp ratio was 0.06 µg/ml and the median value of quinolinic acid was 68.45 ng/ml. A significant correlation between early progression and higher kyn/trp ratio and quinolinic acid concentration was observed (p = 0.017 and p = 0.005, respectively). Patients presenting lower values of kyn/trp ratio and quinolinic acid levels showed longer PFS (median PFS not reached versus 3 months; HR: 0.3; p = 0.018) and OS (median OS not reached vs 3 months; HR: 0.18; p = 0.0005).
IDO activity, expressed as kyn/trp ratio, is associated with response to immunotherapy; in particular, higher kyn/trp ratio could predict resistance to anti-PD-1 treatment. These preliminary results suggest the possibility of using anti-PD-1 plus IDO inhibitor in those patients with high level of kyn/trp ratio.