Can IDO activity predict primary resistance to anti-PD-1 treatment in NSCLC?
Open accessAbstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
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In 26 stage IV NSCLC patients treated with second-line nivolumab, those with early progression within 3 months had significantly higher baseline Kyn to Trp ratios than responders in univariate and multivariate analyses (P=0.017).
“Patients with early disease progression (within 3 months) had significantly higher Kyn to Trp ratios than responders in univariate and multivariate analyses (P = 0.017)151.”
From Gut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy (2023) · cites this paper as [151]
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References 33 · Cited by 124
Research works printed but not linked: 1
- [28]Holmgaard RB Zamarin D Munn DH Wolchok JD Allison JP Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4 J Exp Med. 2013 210 7 1389 1402 10.1084/jem.20130066 23752227 PMC3698523 · DOI
- Authors
- Botticelli, A., Cerbelli, B., Lionetto, L., Zizzari, I., Salati, M., Pisano, A., Federica, M., Simmaco, M., Nuti, M., & Marchetti, P.
- Affiliations
- Azienda Ospedaliera Sant'Andrea (IT)
- Sapienza University of Rome (IT)
- Istituto Dermopatico dell'Immacolata (IT)
- University of Modena and Reggio Emilia (IT)
- Corresponding author
- Botticelli, Andrea
- ORCID
- Venue
- Journal of Translational Medicine
- Published
- 2018-08-06
- Volume
- 16
- Issue
- 1
- Pages
- 219-219
- ISSN
- 1479-5876 (ISSN-L)
- PMC
- PMC6080500
- OpenAlex
- W2887169335
- Cited by
- 124
- References
- 33
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 13 · 2023: 19 · 2022: 20 · 2021: 22 · 2020: 27 · 2019: 10
- FWCI
- 5.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Translational Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Sapienza Università di Roma
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- indoleamine 2,3-dioxygenase, kynurenine/tryptophan ratio, non-small cell lung cancer, anti-PD-1 resistance, nivolumab, immune checkpoint inhibitors, quinolinic acid, serum biomarkers, treatment response prediction, tumor immune microenvironment, progression-free survival, overall survival
- MeSH terms
- Aged, Carcinoma, Non-Small-Cell Lung, Female, Humans, Immunotherapy, Kynurenine, Lung Neoplasms, Male, Tryptophan, Multivariate Analysis, Quinolinic Acid, Disease Progression, Drug Resistance, Neoplasm, Indoleamine-Pyrrole 2,3,-Dioxygenase, Kaplan-Meier Estimate, Programmed Cell Death 1 Receptor
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